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List of phenyltropanes

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List of phenyltropanes

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Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; thus, the phenyl is attached direct to the tropane skeleton (hence the name "phenyl"-tropane) with no further spacer that the cocaine benzoyloxy provided. The original purpose of phenyltropane-related research was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (which stems from the methylated benzoate ester being essential to cocaine's blockage of sodium channels, and which causes topical anesthesia) while retaining stimulant function.

Phenyltropane compounds present promising avenues of research into therapeutic applications, particularly in regard to addiction treatment. These compounds' uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's and Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.) Certain phenyltropanes can even be used as a smoking cessation aid (cf. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-n, for 'cocaine' "analog", or specifically RTI-4229-n of the subsequent numbers given below in this article) Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.

File:Phenyltropane.gif|class=bg-transparent|3D rendering of troparil; which comprises a privileged scaffold of among the phenyltropane class of compounds. File:Troparil structure.png|class=skin-invert-image|Troparil structure: cf.

2-Carboxymethyl esters (phenyl-methyl[[ecgonine]]s)

File:Epibati-tropane.svg|Epibatropane containing a nitrogen heteroatom in the benzene ring formation. File:Tamagnan.png|Tamagnan: SSRI, SERT = 17(pM) = 10 times the strength of paroxetine for 5HT. File:RTI-298.svg|RTI-298 File:RTI-11W.svg|(4′-)para-cis-propenyl-phenyl-methylecgonine. A rare SDRI compound with negligible NET affinity (2,800.0nM displacement value for NET ligand) that retains significant DAT & SERT (15.0nM & 7.1nM) affinity. File:Carroll 15.svg|C2-C3 unsaturated (non-isomeric, neither α nor β orientated) 2-naphthyl-tropane File:Carroll 13.svg|1-naphthyl-tropane in its usual (comparably non-standard) boat formation of its tropane ring.

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.

Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact. The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.

Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

Structure [[File:Phenyltropane 11a-bb.svgx100pxclass=skin-invert-image]]Short Name
*i.e.* Trivial IUPAC
(non-systematic) Name
(*Singh's #*)R (*para*-substitution)
of benzeneDA
[3H]WIN 35428
IC50 nM
(*Ki* nM)5HT
[3H]paroxetine
IC50 nM
(*Ki* nM)NE
[3H]nisoxetine
IC50 nM
(*Ki* nM)selectivity
5-HTT/DATselectivity
NET/DAT
cocaine
(benzoyloxytropane)H102 ± 12
241 ± 18**ɑ**1045 ± 89
112 ± 2**b**3298 ± 293
160 ± 15**c**10.2
0.5**d**32.3
0.7**e**
[[File:Phenyltropane 11a - WIN 35065-2 - Troparil.svgx100pxclass=skin-invert-image]](*para*-hydrogen)phenyltropane
WIN 35,065-2 (β-CPT) Troparil
*11a*H23 ± 5.0
49.8 ± 2.2**ɑ**1962 ± 61
173 ± 13**b**920 ± 73
37.2 ± 5.2**c**85.3
3.5**d**40.0
0.7**e**
[[File:Phenyltropane 11b - WIN 35428.svgx100pxclass=skin-invert-image]]*para*-fluorophenyltropane
WIN 35,428 (β-CFT)
*11b*F14 (15.7 ± 1.4)
22.9 ± 0.4**ɑ**156 (810 ± 59)
100 ± 13**b**85 (835 ± 45)
38.6 ± 9.9**c**51.6
4.4**d**53.2
1.7**e**
[[File:Phenyltropane 11k.svgx100pxclass=skin-invert-image]]*para*-nitrophenyltropane
*11k*NO210.1 ± 0.10????
[[File:Phenyltropane 11j.svgx100pxclass=skin-invert-image]]*para*-aminophenyltropane
RTI-29
*11j*NH29.8
24.8 ± 1.3**g**5110151521.415.4
[[File:Phenyltropane 11c.svgx100pxclass=skin-invert-image]]*para*-chlorophenyltropane
RTI-31
*11c*Cl1.12 ± 0.06
3.68 ± 0.09**ɑ**44.5 ± 1.3
5.00 ± 0.05**b**37 ± 2.1
5.86 ± 0.67**c**39.7
1.3**d**33.0
1.7**e**
[[File:Phenyltropane 11f.svgx100pxclass=skin-invert-image]]*para*-methylphenyltropane
RTI-32 Tolpane
*11f*Me1.71 ± 0.30
7.02 ± 0.30**ɑ**240 ± 27
19.38 ± 0.65**b**60 ± 0.53**e**
8.42 ± 1.53**c**140
2.8**d**35.1
1.2**e**
[[File:Phenyltropane 11d.svgx100pxclass=skin-invert-image]]*para*-bromophenyltropane
RTI-51 Bromopane
*11d*Br1.81 (1.69) ± 0.3010.6 ± 0.2437.4 ± 5.25.820.7
[[File:Phenyltropane 11e - RTI-55.svgx100pxclass=skin-invert-image]]*para*-iodophenyltropane
RTI-55 (β-CIT) Iometopane
*11e*I1.26 ± 0.04
1.96 ± 0.09**ɑ**4.21 ± 0.3
1.74 ± 0.23**b**36 ± 2.7
7.51 ± 0.82**c**3.3
0.9**d**28.6
3.8**e**
[[File:Phenyltropane 11h.svgx100pxclass=skin-invert-image]]*para*-hydroxyphenyltropane
*11h*OH12.1 ± 0.86————
[[File:Phenyltropane 11i.svgx100pxclass=skin-invert-image]]*para*-methoxyphenyltropane
*11i*OCH38.14 ± 1.3————
[[File:Phenyltropane 11l.svgx100pxclass=skin-invert-image]]*para*-azidophenyltropane
*11l*N32.12 ± 0.13————
[[File:Phenyltropane 11m.svgx100pxclass=skin-invert-image]]*para*-trifluoromethylphenyltropane
*11m*CF313.1 ± 2.2————
[[File:Phenyltropane 11n.svgx100pxclass=skin-invert-image]]*para*-acetylaminophenyltropane
*11n*NHCOCH364.2 ± 2.6————
[[File:Phenyltropane 11o.svgx100pxclass=skin-invert-image]]*para*-propionylaminophenyltropane
*11o*NHCOC2H5121 ± 2.7————
[[File:Phenyltropane 11p.svgx100pxclass=skin-invert-image]]*para*-ethoxycarbonylaminophenyltropane
*11p*NHCO2C3H5316 ± 48————
[[File:Phenyltropane 11q.svgx100pxclass=skin-invert-image]]*para*-trimethylstannylphenyltropane
*11q*Sn(CH3)3144 ± 37————
[[File:Phenyltropane 11g.svgx100pxclass=skin-invert-image]]*para*-ethylphenyltropane
RTI-83
*11g*Et55 ± 2.128.4 ± 3.8
(2.58 ± 3.5)4030 (3910) ± 381
(2360 ± 230)0.573.3
[[File:Phenyltropane 11r.svgx100pxclass=skin-invert-image]]*para*-*n*-propylphenyltropane
RTI-282**i**
*11r**n*-C3H768.5 ± 7.170.4 ± 4.13920 ± 1301.057.2
[[File:Phenyltropane 11s.svgx100pxclass=skin-invert-image]]*para*-isopropylphenyltropane
*11s*CH(CH3)2597 ± 52191 ± 9.575000 ± 58200.3126
[[File:Phenyltropane 11t.svgx100pxclass=skin-invert-image]]*para*-vinylphenyltropane
RTI-359
*11t*CH-CH21.24 ± 0.29.5 ± 0.878 ± 4.17.762.9
[[File:Phenyltropane 11u.svgx100pxclass=skin-invert-image]]*para*-methylethenylphenyltropane
RTI-283**j**
*11u*C(=CH2)CH314.4 ± 0.33.13 ± 0.161330 ± 3330.292.4
[[File:Phenyltropane 11v.svgx100pxclass=skin-invert-image]]*para*-*trans*-propenylphenyltropane
RTI-296**i**
*11v**trans*-CH=CHCH35.29 ± 0.5311.4 ± 0.281590 ± 932.1300
[[File:Phenyltropane 11x.svgx100pxclass=skin-invert-image]]*para*-allylphenyltropane
*11x*CH2CH=CH232.8 ± 3.128.4 ± 2.42480 ± 2290.975.6
[[File:Phenyltropane 11y.svgx100pxclass=skin-invert-image]]*para*-ethynylphenyltropane
RTI-360
*11y*C≡CH1.2 ± 0.14.4 ± 0.483.2 ± 2.83.769.3
[[File:Phenyltropane 11z.svgx100pxclass=skin-invert-image]]*para*-propynylphenyltropane
RTI-281**i**
*11z*C≡CCH32.37 ± 0.215.7 ± 1.5820 ± 466.6346
[[File:Phenyltropane 11w.svgx100pxclass=skin-invert-image]]*para*-*cis*-propenylphenyltropane
RTI-304
*11w**cis*-CH=CHCH315 ± 1.27.1 ± 0.712,800**k** ± 3000.5186.6**k**
[[File:Phenyltropane carroll 7a.svgx140pxclass=skin-invert-image]]*para*-(*Z*)-phenylethenylphenyltropane*cis*-CH=CHPh11.7 ± 1.12————
[[File:Phenyltropane carroll 6b.svgx100pxclass=skin-invert-image]]*para*-benzylphenyltropane-CH2-Ph526 ± 657,240 ± 390
(658 ± 35)6670 ± 377
(606 ± 277)13.712.6
[[File:Phenyltropane carroll 6c.svgx100pxclass=skin-invert-image]]*para*-phenylethenylphenyltropaneCH2
║
-C-Ph474 ± 1332,710 ± 800
(246 ± 73)7,060 ± 1,760
(4,260 ± 1,060)5.714.8
[[File:Phenyltropane carroll 5a.svgx100pxclass=skin-invert-image]]*para*-phenylethylphenyltropane**l**-(CH2)2-Ph5.14 ± 0.63234 ± 26
(21.3 ± 2.4)10.8 ± 0.3
(6.50 ± 0.20)45.52.1
[[File:RTI-436.svgx100pxclass=skin-invert-image]]*para*-(*E*)-phenylethenylphenyltropane**l**
RTI-436*trans*–CH=CHPh3.09 ± 0.75335 ± 150
(30.5 ± 13.6)1960 ± 383
(1180 ± 231)108.4634.3
[[File:Phenyltropane carroll 5b.svgx120pxclass=skin-invert-image]]*para*-phenylpropylphenyltropane**l**-(CH2)3-Ph351 ± 521,243 ± 381
(113 ± 35)14,200 ± 1,800
(8,500 ± 1,100)3.540.4
[[File:Phenyltropane carroll 8.svgx120pxclass=skin-invert-image]]*para*-phenylpropenylphenyltropane**l**-CH=CH-CH2-Ph15.8 ± 1.31781 ± 258
(71 ± 24)1,250 ± 100
(759 ± 60)49.479.1
[[File:Phenyltropane carroll 5c.svgx100pxclass=skin-invert-image]]*para*-phenylbutylphenyltropane**l**-(CH2)4-Ph228 ± 214,824 ± 170
(439 ± 16)2,310 ± 293
(1,390 ± 177)21.110.1
[[File:RTI-298 structure.svgx100pxclass=skin-invert-image]]*para*-phenylethynylphenyltropane**l**
RTI-298{{Cite journalpmid = 12190324year = 2002first1 = B. E.last2 = Keverlinelast3 = Nielast4 = Navarro
[[File:Phenyltropane Carroll 4b.svgx100pxclass=skin-invert-image]]doi=10.1021/jm020098npmid=12190324title=Synthesis and Transporter Binding Properties of 3β-[4'-(Phenylalkyl, -phenylalkenyl, and -phenylalkynl)phenyl]tropane-2β-carboxylic Acid Methyl Esters: Evidence of a Remote Phenyl Binding Domain on the Dopamine Transporterjournal=Journal of Medicinal Chemistryvolume=45issue=18pages=4029–37year=2002last1=Bloughfirst1=Bruce E.last2=Keverlinefirst2=Kathryn I.last3=Niefirst3=Zhelast4=Navarrofirst4=Hernánlast5=Kuharfirst5=Michael J.last6=Carrollfirst6=F. Ivy}}–C≡C-CH2Ph1.82 ± 0.4213.1 ± 1.7
(1.19 ± 0.42)27.4 ± 2.6
(16.5 ± 1.6)7.115
[[File:RTI-430.svgx100pxclass=skin-invert-image]]*para*-phenylbutynylphenyltropane**l**
RTI-430–C≡C(CH2)2Ph6.28 ± 1.252180 ± 345
(198 ± 31)1470 ± 109
(885 ± 66)347.1234
[[File:Phenyltropane carroll 4d.svgx100pxclass=skin-invert-image]]*para*-phenylpentynylphenyltropane**l**–C≡C-(CH2)3-Ph300 ± 371,340 ± 232
(122 ± 21)4,450 ± 637
(2,680 ± 384)4.4614.8
[[File:Para-trimethylsilylethynyl-phenyltropane.svgx100pxclass=skin-invert-image]]*para*-trimethylsilylethynylphenyltropane——————
[[File:Para-hydroxypropynyl-phenyltropane.svgx100pxclass=skin-invert-image]]*para*-hydroxypropynylphenyltropane——————
[[File:Phenyltropane carroll 4e.svgx100pxclass=skin-invert-image]]*para*-hydroxyhexynylphenyltropane**l**–C≡C-(CH2)4OH57 ± 4828 ± 29
(75 ± 2.6)9,500 ± 812
(5,720 ± 489)14.5166.6
[[File:Tamagnan.svgx100pxclass=skin-invert-image]]*para*-(thiophen-3-yl)phenyltropane
Tamagnan*p*-thiophene120.0171890.00141615.7
[[File:Phenyltropane 11aa.svgx100pxclass=skin-invert-image]]*para*-biphenyltropane
*11aa*Ph10.3 ± 2.6**f**
29.4 ± 3.8**ɑ**
15.6 ± 0.695.8 ± 36
(8.7 ± 3.3)1,480 ± 269
(892 ± 162)6.194.8
[[File:Phenyltropane 11bb.svgx110pxclass=skin-invert-image]]3β-2-naphthyltropane
RTI-318
*11bb*3β-2-naphthyl0.51 ± 0.03
3.32 ± 0.08**f**
3.53 ± 0.09**ɑ**0.80 ± 0.06
(0.07 ± 0.1)21.1 ± 1.0
(12.7 ± 0.60)1.541.3
[[File:Phenyltropane 15.svgx100pxclass=skin-invert-image]]*para*-bimethoxyphenyltropane
*15*OCH2OCH3**h**—————

(4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes

Compound structureAlphanumeric code
(name)*para*-substitutionN8SERTDATNETSelectivity
SERT versus DATSelectivity
SERT versus NET
1
(cocaine)(—)-CocaineCH310508933200.083.2
2
(β-CIT), (Iometopane)IodoCH30.46 ± 0.060.96 ± 0.152.80 ± 0.402.16.1
(*R*,*S*-Citalopram)——1.6016,5406,19010,3383,869
[[File:Tamagnan 4a.svgx100pxclass=skin-invert-image]]4a2-ThiopheneCH30.15 ± 0.01552 ± 12.8158 ± 123461,053
[[File:Tamagnan.svgx100pxclass=skin-invert-image]]4b
(Tamagnan)3-ThiopheneCH30.017 ± 0.00412.1 ± 3189 ± 8271011,118
[[File:Tamagnan 4c.svgx100pxclass=skin-invert-image]]4c2-(5-Br)-ThiopheneCH30.38 ± 0.0086.43 ± 0.9324 ± 1917853
[[File:Tamagnan 4d.svgx100pxclass=skin-invert-image]]4d2-(5-Cl)-ThiopheneCH30.64 ± 0.044.42 ± 1.64311 ± 256.9486
[[File:Tamagnan 4e.svgx100pxclass=skin-invert-image]]4e2-(5-I)-ThiopheneCH34.56 ± 0.8422.1 ± 3.21,137 ± 1234.9249
[[File:Tamagnan 4f.svgx100pxclass=skin-invert-image]]4f2-(5-NH2)-ThiopheneCH364.7 ± 3.710,00030,000155464
[[File:Tamagnan 4g.svgx100pxclass=skin-invert-image]]4g2-(4,5-NO2)-ThiopheneCH35,00030,00010,0006.02.0
[[File:Tamagnan 4h.svgx100pxclass=skin-invert-image]]4h3-(4-Br)-ThiopheneCH34.02 ± 0.34183 ± 6910,000462,488
[[File:Tamagnan 5a.svgx100pxclass=skin-invert-image]]5a2-ThiopheneH0.11 ± 0.00612.2 ± 0.975.3 ± 9.6111685
[[File:Tamagnan 5b.svgx100pxclass=skin-invert-image]]5b3-ThiopheneH0.23 ± 0.026.4 ± 0.2739 ± 0.828170

(3′,4′-Disubstituted phenyl)-tropanes

File:RTI-318 structure.png File:RTIthreefivethree.png File:Phenyltropane 17c.svg File:RTI-112.svg

Compound
*(+ S. Singh's name)*X
(4′-*para*)Y
(3′-*meta*)2 Positionconfig8DA5-HTNE
RTI-318
*11bb*β-naphthylCO2Meβ,βNMe0.50.8120
Dichloropane (RTI-111**ɑ**)
*17c*ClClCO2Meβ,βNMe0.793.1318.0
RTI-88 [recheck]
*17e*NH2ICO2Meβ,βNMe1.351329**c**320**c**
RTI-97
*17d*NH2BrCO2Meβ,βNMe3.91181282
RTI-112**b**
*17b*ClMeCO2Meβ,βNMe0.8210.536.2
RTI-96
*17a*FMeCO2Meβ,βNMe2.9576520
RTI-295EtICO2Meβ,βNMe21.32.961349
RTI-353 (EINT)EtICO2Meβ,βNH3310.69148
RTI-279MeICO2Meβ,βNH5.981.0674.3
RTI-280MeICO2Meβ,βNMe3.126.81484
doi = 10.1016/j.bmcl.2003.07.014pmid = 14592523title = Synthesis and biological activity of 2-Carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanesjournal = Bioorganic & Medicinal Chemistry Lettersvolume = 13issue = 22pages = 4133–4137year = 2003last1 = Meltzerfirst1 = P. C.last2 = McPheefirst2 = M.last3 = Madrasfirst3 = B. K. }}catecholCO2Meβ,βNMe100??
MeltzerOAcOAcCO2Meβ,βNMe???
  • ɑas ·HCl (salt)
  • bas ·HCl·2 H2O (salt)
  • cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT
Compound [[File:Phenyltropane 16-17.svg150pxclass=skin-invert-image]]Short Name
(S. Singh)R2R1DA5HTNESelectivity
5-HTT/DATSelectivity
NET/DAT
[[File:Phenyltropane 16a.svg150pxclass=skin-invert-image]]*meta*-fluorophenyltropane
16aFH23 ± 7.8----
[[File:Phenyltropane 16b.svg150pxclass=skin-invert-image]]*meta*-chlorophenyltropane
16bClH10.6 ± 1.8----
[[File:Phenyltropane 16c.svg150pxclass=skin-invert-image]]*meta*-bromophenyltropane
16cBrH7.93 ± 0.08ɑ----
[[File:Phenyltropane 16d.svg150pxclass=skin-invert-image]]*meta*-iodophenyltropane
16dIH26.1 ± 1.7----
[[File:Phenyltropane 16e.svg160pxclass=skin-invert-image]]*meta*-tributylstannylphenyltropane
16eSnBu3H1100 ± 170----
[[File:Methyl (1R,2S,3S,5S)-3-(3-ethynylphenyl)-8-methyl-8-azabicyclo(3.2.1)octane-2-carboxylate.svg160pxclass=skin-invert-image]]*meta*-ethynylphenyltropaneC≡CHH-----
[[File:Phenyltropane 17a.svg150pxclass=skin-invert-image]]*meta*-methyl-*para*-fluorophenyltropane
RTI-96
17aCH3F2.95 ± 0.58----
[[File:RTI-112.svg150pxclass=skin-invert-image]]*meta*-methyl-*para*-chlorophenyltropane
RTI-112**c**
17bCH3Cl0.81 ± 0.0510.5 ± 0.0536.2 ± 1.013.044.7
[[File:Phenyltropane 17c.svg150pxclass=skin-invert-image]]doi=10.1021/jm00059a010pmid=8464040title=Substituted 3-phenyltropane analogs of cocaine: Synthesis, inhibition of binding at cocaine recognition sites, and positron emission tomography imagingjournal=Journal of Medicinal Chemistryvolume=36issue=7pages=855–62year=1993last1=Meltzerfirst1=P. C.last2=Liangfirst2=A. Y.last3=Brownellfirst3=A. L.last4=Elmalehfirst4=D. R.last5=Madrasfirst5=B. K.}} Dichloropane
17cClCl0.79 ± 0.08**b**3.13 ± 0.36**b**18.0 ± 0.8
17.96 ± 0.85**b''''''d**4.0**b**22.8**b**
[[File:Phenyltropane 17d.svg160pxclass=skin-invert-image]]*meta*-bromo-*para*-aminophenyltropane
RTI-97
17dBrNH23.91 ± 0.5918128246.272.1
[[File:Phenyltropane 17e.svg160pxclass=skin-invert-image]]*meta*-iodo-*para*-aminophenyltropane
RTI-88
17eINH21.35 ± 0.11120 ± 41329 ± 12488.9984
[[File:Phenyltropane 17f.svg160pxclass=skin-invert-image]]*meta*-iodo-*para*-azidophenyltropane
17fIN34.93 ± 0.32----
  • ɑIC50 determined in Cynomolgous monkey caudate-putamen
  • bas ·HCl (salt)
  • cas ·HCl·2 H2O (salt)
  • dNEN
Structure [[File:Di-subst thio sulfonyl phenyltropanes.png150pxclass=skin-invert-image]]CompoundRXnInhibition of [3H]WIN 35,428
@ DAT
IC50 (nM)Inhibition of [3H]Paroxetine
@ 5-HTT
K*i* (nM)Inhibition of [3H]Nisoxetine
@ NET
K*i* (nM)NET/DAT
(uptake ratio)NET/5-HTT
(uptake ratio)
CocaineDes-thio/sulfinyl/sulfonyl
HHDesmethyl
089.19519902221
*para*-methoxyphenyltropane
Singh: *11i*Des-thio/sulfinyl/sulfonyl
OCH3H06.5 ± 1.34.3 ± 0.51110 ± 64171258
[[File:Sulfur containing phenyltropane 7a.svg190pxclass=skin-invert-image]]7aCH3H09 ± 30.7 ± 0.2220 ± 1024314
[[File:Sulfur containing phenyltropane 7b.svg200pxclass=skin-invert-image]]7bC2H5H0232 ± 344.5 ± 0.51170 ± 3005260
[[File:Sulfur containing phenyltropane 7c.svg200pxclass=skin-invert-image]]7cCH(CH3)2H016 ± 223 ± 2129 ± 287
[[File:Sulfur containing phenyltropane 7d.svg200pxclass=skin-invert-image]]7dCF3H0200 ± 708 ± 21900 ± 30010238
[[File:Sulfur containing phenyltropane 7e.svg180pxclass=skin-invert-image]]7eCH3Br010.1 ± 10.6 ± 0.2121 ± 1212202
[[File:Sulfur containing phenyltropane 7f.svg180pxclass=skin-invert-image]]7fCH3Br176 ± 183.2 ± 0.4690 ± 809216
[[File:Sulfur containing phenyltropane 7g.svg180pxclass=skin-invert-image]]7gCH3H191 ± 164.3 ± 0.6515 ± 606120
[[File:Sulfur containing phenyltropane 7h.svg180pxclass=skin-invert-image]]7hCH3H210,000208 ± 4510,000148

(2′,4′-Disubstituted phenyl)-tropanes

Compound structure
[[File:Phenyltropane 2,4-subst.svgx130pxclass=skin-invert-image]]Trivial IUPAC
(non-systematic)
NameR2
*ortho*R1
*para*DA5HTNESelectivity
5-HTT/DATSelectivity
NET/DAT
[[File:Ortho-para-nitro-phenyltropane.svg185pxclass=skin-invert-image]]*ortho*,*para*-dinitrophenyltropaneNO2NO2-----

(3′,4′,5′-Trisubstituted ''para''-methoxyphenyl)-tropanes

Structure
[[File:Phenyltropanes Carroll generic.svg210pxclass=skin-invert-image]]DAT
IC50
(compound #)125-HTT
*Ki*
ParoxetineNET
*Ki*
NisoxetineSelectivity
NET/DAT
Ratio
*Ki*/IC50Selectivity
NET/5-HTT
Ratio
*Ki*/*Ki*
Cocaine---89.1
6
*RTI-112*---0.82 ± 0.05
[[File:Cocaine analog Carroll 7a.svg200pxleftclass=skin-invert-image]]7a
*11i*HHCH36.5 ± 1.3
[[File:Cocaine analog Carroll 7b.svg230pxleftclass=skin-invert-image]]7bHHC2H592 ± 8
[[File:Cocaine analog Carroll 7c.svg200pxleftclass=skin-invert-image]]7cFHCH316 ± 1
[[File:Cocaine analog Carroll 7d.svg200pxleftclass=skin-invert-image]]7dBrHCH347 ± 15
[[File:Cocaine analog Carroll 7f.svg200pxleftclass=skin-invert-image]]7fBrBrCH392 ± 22
[[File:Cocaine analog Carroll 7e.svg210pxleftclass=skin-invert-image]]7eIHCH3170 ± 60
[[File:Cocaine analog Carroll 7g.svg200pxleftclass=skin-invert-image]]7gIICH31300 ± 200

ɑN=2

(2′,4′,5′-Trisubstituted phenyl)-tropanes

StructureShort NameSelectivity
NET/DAT
RatioSelectivity
NET/5-HTT
Ratio
[[File:Methyl (1R,2S,3S,5S)-3-(4-ethyl-2,5-diiodophenyl)-8-methyl-8-azabicyclo(3.2.1)octane-2-carboxylate.svgx130pxclass=skin-invert-image]]*para*-ethyl-*ortho, meta*-diiodophenyltropaneiodoethyl

2-Carbmethoxy modified (replaced/substituted)

General 2-carbmethoxy modifications

2β-substitutions of ''p''-methoxy-phenyltropanes

Structure
[[File:Phenyltropane generic ester.svg200pxclass=skin-invert-image]]CO2*R* (2β-substituted)
(compound 9 is 2β=*R*)DAT
IC50
(compound #)125-HTT
*Ki*
ParoxetineNET
*Ki*
NisoxetineSelectivity
NET/DAT
Ratio
*Ki*/IC50Selectivity
NET/5-HTT
Ratio
*Ki*/*Ki*
[[File:Cocaine analog Carroll 7a.svg200pxleftclass=skin-invert-image]]7a
*11i*CH36.5 ± 1.34.3 ± 0.51110 ± 64171
[[File:Cocaine analog Carrol 8a.svg200pxleftclass=skin-invert-image]]8a(CH3)2CH14 ± 3135 ± 352010 ± 200144
[[File:Cocaine analog Carrol 8b.svg200pxleftclass=skin-invert-image]]8bcyclopropane6.0 ± 229 ± 31230 ± 140205
[[File:Cocaine analog Carrol 8c.svg200pxleftclass=skin-invert-image]]8ccyclobutane13 ± 3100 ± 83000231
[[File:Cocaine analog Carrol 8d.svg220pxleftclass=skin-invert-image]]8dO2N...1,4-xylene...(CH2)242 ± 82.9 ± 0.2330 ± 208
[[File:Cocaine analog Carrol 8e.svg220pxleftclass=skin-invert-image]]8eH2N...1,4-xylene...(CH2)27.0 ± 28.3 ± 0.42200 ± 300ɑ314
[[File:Cocaine analog Carrol 8f.svg250pxleftclass=skin-invert-image]]8fCH3CONH...1,4-xylene...(CH2)26.0 ± 15.5 ± 0.51460 ± 30243
[[File:Cocaine analog Carrol 8g.svg230pxleftclass=skin-invert-image]]8gH2N...2-bromo-1,4-dimethylbenzene...(CH2)23.3 ± 1.44.1 ± 0.61850 ± 90561
[[File:Cocaine analog Carrol 8h.svg230pxleftclass=skin-invert-image]]8hH2N...1,3-dibromo-2,5-dimethylbenzene...(CH2)215 ± 62.0 ± 0.42710 ± 250ɑ181
[[File:Cocaine analog Carrol 8i.svg220pxleftclass=skin-invert-image]]8iH2N...2-iodo-1,4-dimethylbenzene...(CH2)22.5 ± 0.73.5 ± 12040 ± 300ɑ816
[[File:Cocaine analog Carrol 8j.svg230pxleftclass=skin-invert-image]]8jH2N...1,3-diiodo-2,5-dimethylbenzene...(CH2)2102 ± 151.0 ± 0.12600 ± 200ɑ25
[[File:Cocaine analog Carroll 9.svg210pxleftclass=skin-invert-image]]93-(4-methylphenyl)-1,2-oxazole18 ± 6860 ± 1703000167

ɑN=2

2β-carboxy side-chained (''p''-chloro/iodo/methyl) phenyltropanes

Compound
[[File:Phenyltropane generic subst.svg150pxclass=skin-invert-image]]Short Name
(S. Singh)RXIC50 (nM)
DAT
[3H]WIN 35428IC50 (nM)
5-HTT
[3H]paroxetineIC50 (nM)
NET
[3H]nisoxetineSelectivity
5-HTT/DATSelectivity
NET/DAT
[[File:Phenyltropane 23a.svgx100pxclass=skin-invert-image]]23aCH(CH3)2H85.1 ± 2.523121 ± 397632047 ± 1491272376
[[File:Phenyltropane 23b.svgx120pxclass=skin-invert-image]]23bC6H5H76.7 ± 3.6106149 ± 725619262 ± 5931384251
[[File:Phenyltropane 24a.svgx100pxclass=skin-invert-image]]24aCH(CH3)2Cl1.4 ± 0.13
6.04 ± 0.31**ɑ**1400 ± 7
128 ± 15**b**778 ± 21
250 ± 0.9**c**1000
21.2**d**556
41.4**e**
[[File:Phenyltropane 24b.svgx100pxclass=skin-invert-image]]24bcyclopropylCl0.96 ± 0.10168 ± 1.8235 ± 8.39175245
[[File:Phenyltropane 24c.svgx120pxclass=skin-invert-image]]24cC6H5Cl1.99 ± 0.05
5.25 ± 0.76**ɑ**2340 ± 27
390 ± 34**b**2960 ± 220
242 ± 30**c**1176
74.3**d**1.3
41.6**e**
[[File:Phenyltropane 24d.svgx150pxclass=skin-invert-image]]24dC6H4-4-ICl32.6 ± 3.91227 ± 176967.6 ± 26.337.629.7
[[File:Phenyltropane 24e.svgx120pxclass=skin-invert-image]]24eC6H4-3-CH3Cl9.37 ± 0.522153 ± 1432744 ± 140230293
[[File:Phenyltropane 24f.svgx140pxclass=skin-invert-image]]24fC6H4-4-CH3Cl27.4 ± 1.51203 ± 421277 ± 11843.946.6
[[File:Phenyltropane 24g.svgx120pxclass=skin-invert-image]]24gC6H4-2-CH3Cl3.91 ± 0.233772 ± 3844783 ± 3879651223
[[File:Phenyltropane 24h.svgx140pxclass=skin-invert-image]]24hC6H4-4-ClCl55 ± 2.316914 ± 10564883 ± 28830788.8
[[File:Phenyltropane 24i.svgx150pxclass=skin-invert-image]]24iC6H4-4-OCH3Cl71 ± 5.619689 ± 18431522 ± 9427721.4
[[File:Phenyltropane 24j.svgx150pxclass=skin-invert-image]]24j(CH2)2C6H4-4-NO2Cl2.71 ± 0.13----
[[File:Phenyltropane 24k.svgx150pxclass=skin-invert-image]]24k(CH)2C6H4-4-NH2Cl2.16 ± 0.25----
[[File:Phenyltropane 24l.svgx150pxclass=skin-invert-image]]24l(CH2)2C6H3-3-I-4-NH2Cl2.51 ± 0.25----
[[File:Phenyltropane 24m.svgx150pxclass=skin-invert-image]]24m(CH2)2C6H3-3-I-4-N3Cl14.5 ± 0.94----
[[File:Phenyltropane 24n.svgx150pxclass=skin-invert-image]]24n(CH2)2C6H4-4-N3Cl6.17 ± 0.57----
[[File:Phenyltropane 24o.svgx150pxclass=skin-invert-image]]24o(CH2)2C6H4-4-NCSCl5.3 ± 0.6----
[[File:Phenyltropane 24p.svgx170pxclass=skin-invert-image]]24p(CH2)2C6H4-4-NHCOCH2BrCl1.73 ± 0.06----
[[File:Phenyltropane 25a.svgx100pxclass=skin-invert-image]]25aCH(CH3)2I0.43 ± 0.05
2.79 ± 0.13**ɑ**66.8 ± 6.53
12.5 ± 1.0**b**285 ± 7.6
41.2 ± 3.0**c**155
4.5**d**663
14.8**e**
[[File:Phenyltropane 25b.svgx100pxclass=skin-invert-image]]25bcyclopropylI0.61 ± 0.0815.5 ± 0.72102 ± 1125.4167
[[File:Phenyltropane 25c.svgx120pxclass=skin-invert-image]]25cC6H5I1.51 ± 0.34
6.85 ± 0.93**ɑ**184 ± 22
51.6 ± 6.2**b**3791 ± 149
32.7 ± 4.4**c**122
7.5**d**2510
4.8**e**
[[File:Phenyltropane 26a.svgx100pxclass=skin-invert-image]]26aCH(CH3)2CH36.45 ± 0.85
15.3 ± 2.08**ɑ**6090 ± 488
917 ± 54**b**1926 ± 38
73.4 ± 11.6**c**944
59.9**d**299
4.8**e**
[[File:Phenyltropane 26b.svgx120pxclass=skin-invert-image]]26bCH(C2H5)2CH319.1 ± 14499 ± 5573444 ± 44235180
[[File:Phenyltropane 26c.svgx100pxclass=skin-invert-image]]26ccyclopropylCH317.8 ± 0.76485 ± 212628 ± 25227.2148
[[File:Phenyltropane 26d.svgx110pxclass=skin-invert-image]]26dcyclobutylCH33.74 ± 0.522019 ± 1334738 ± 3225401267
[[File:Phenyltropane 26e.svgx120pxclass=skin-invert-image]]26ecyclopentylCH31.68 ± 0.141066 ± 109644 ± 28634383
[[File:Phenyltropane 26f.svgx120pxclass=skin-invert-image]]26fC6H5CH33.27 ± 0.06
9.13 ± 0.79**ɑ**24500 ± 1526
1537 ± 101**b**5830 ± 370
277 ± 23**c**7492
168**d**1783
30.3**e**
[[File:Phenyltropane 26g.svgx120pxclass=skin-invert-image]]26gC6H4-3-CH3CH38.19 ± 0.905237 ± 4532136 ± 208639261
[[File:Phenyltropane 26h.svgx140pxclass=skin-invert-image]]26hC6H4-4-CH3CH381.2 ± 1615954 ± 6144096 ± 12119650.4
[[File:Phenyltropane 26i.svgx120pxclass=skin-invert-image]]26iC6H4-2-CH3CH323.2 ± 0.9711040 ± 50425695 ± 13944761107
[[File:Phenyltropane 26j.svgx150pxclass=skin-invert-image]]26jC6H4-4-ClCH3117 ± 7.942761 ± 23999519 ± 86436581.3
[[File:Phenyltropane 26k.svgx150pxclass=skin-invert-image]]26kC6H4-4-OCH3CH395.6 ± 8.882316 ± 78523151 ± 28286133.0
  • ɑKi value for displacement of [3H]DA uptake.
  • bKi value for displacement of [3H]5-HT uptake.
  • cKi value for displacement of [3H]NE uptake.
  • d[3H]5-HT uptake to [3H]DA uptake ratio.
  • e[3H]NE uptake to [3H]DA uptake ratio.

Carboxyaryl

CompoundX2 Positionconfig8DA5-HTNE
RTI-122I-CO2Phβ,βNMe1.501843,791
RTI-113Cl-CO2Phβ,βNMe1.982,3362,955
RTI-277NO2-CO2Phβ,βNMe5.942,9105,695
RTI-120 [recheck]Me-CO2Phβ,βNMe3.2624,4715,833
RTI-116Cl-CO2(*p*-C6H4I)β,βNMe331,227968
RTI-203ClCO2(*m*-C6H4Me)β,βNMe9.3721532744
RTI-204Cl-CO2(*o*-C6H4Me)β,βNMe3.913,7724,783
RTI-205Me-CO2(*m*-C6H4Me)β,βNMe8.195,2372,137
RTI-206Cl-CO2(*p*-C6H4Me)β,βNMe27.41,2031,278

2-Phenyl-3-Phenyltropanes

Compound StructureX
(*para*)DAT
[3H]WIN 35428 IC50 (nM)DAT
[3H]Mazindol *Ki* (nM)5-HTT
[3H]Paroxetine IC50 (nM)[3H]DA uptake *Ki* (nM)[3H]5-HT uptake *Ki* (nM)Selectivity
[3H]5-HT/[3H]DA
Cocaine(2β,3β)(H)89 ± 4.82811050 ± 89423
[[File:Singh 67a.svgx105pxclass=skin-invert-image]]67a2β,3βH12.6 ± 1.814.921000 ± 332028.9
[[File:Singh 67b.svgx155pxclass=skin-invert-image]]67b2β,3αH-13.8-11.7
[[File:Singh 67c.svgx135pxclass=skin-invert-image]]67c2α,3αH690 ± 37-41300 ± 5300-
[[File:Singh 68.svgx170pxclass=skin-invert-image]]682β,3αF-6.00-4.58
[[File:Singh 69a.svgx100pxclass=skin-invert-image]]69a2β,3βCH31.96 ± 0.082.5811000 ± 832.87
[[File:Singh 69b.svgx170pxclass=skin-invert-image]]69b2β,3αCH3-2.87-4.16
[[File:Singh 69c.svgx145pxclass=skin-invert-image]]69c2α,3αCH3429 ± 59-15800 ± 3740-

Carboxyalkyl

File:RTI-77 structure.png File:RTI-121.png File:RTI-150.svg

CodeX2 Positionconfig8DA5-HTNE
RTI-77ClCH2C2(3-iodo-*p*-anilino)β,βNMe2.51—2247
RTI-121 IPCITI-CO2Priβ,βNMe0.4366.8285
RTI-153I-CO2Priβ,βNH1.063.59132
RTI-191I-CO2Prcycβ,βNMe0.6115.5102
RTI-114Cl-CO2Priβ,βNMe1.401,404778
RTI-278NO2-CO2Priβ,βNMe8.142,1474,095
RTI-190Cl-CO2Prcycβ,βNMe0.96168235
RTI-193Me-CO2Prcycβ,βNMe1.681,066644
RTI-117Me-CO2Priβ,βNMe6.456,0901,926
RTI-150Me-CO2Bucycβ,βNMe3.742,0204,738
RTI-127Me-CO2C(H)Et2β,βNMe1945003444
RTI-338ethyl-CO2C2Phβ,βNMe11047.413366

Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.

2-Alkyl Esters & Ethers

Esters (2-Alkyl)
StructureShort Name
(S. Singh)2β=R*Ki* (nM)
DAT
[3H]WIN 35428IC50 (nM)
[3H]DA uptakeSelectivity
uptake/binding
[[File:Singh 59a.svgx110pxclass=skin-invert-image]]59aCH=CHCO2CH322 ± 2123 ± 655.6
[[File:Singh 59b.svgx110pxclass=skin-invert-image]]59bCH2CH2CO2CH323 ± 2166 ± 687.2
[[File:Singh 59c.svgx120pxclass=skin-invert-image]]59c(CH2)2CH=CHCO2CH320 ± 2203 ± 7710.1
[[File:Singh 59d.svgx120pxclass=skin-invert-image]]59d(CH22)4CO2CH330 ± 2130 ± 74.3
[[File:Singh 59e.svgx90pxclass=skin-invert-image]]59eCH=CHCH2OH26 ± 3159 ± 436.1
[[File:Singh 59f.svgx90pxclass=skin-invert-image]]59fCH2CH2CH2OH11 ± 164 ± 325.8
[[File:Singh 59g.svgx110pxclass=skin-invert-image]]59gCH2CH2COC6H528 ± 247 ± 151.7
Ethers (2-Alkyl)
Molecular StructureShort Name
(S. Singh)DAT
[3H]WIN 35428 IC50 (nM)5-HTT
[3H]Paroxetine IC50 (nM)NET
[3H]Nisoxetine IC50 (nM)Selectivity
5-HTT/DATSelectivity
NET/DAT
Paroxetine623 ± 250.28 ± 0.02535 ± 150.0004
[[File:Singh 60a.svgx130pxclass=skin-invert-image]]*R*-60a2β,3β308 ± 20294 ± 185300 ± 4500.9
[[File:Singh 60b.svgx115pxclass=skin-invert-image]]*R*-60b2α,3β172 ± 8.852.9 ± 3.626600 ± 12000.3
[[File:Singh 60c.svgx195pxclass=skin-invert-image]]*R*-60c2β,3α3.01 ± 0.242.2 ± 16123 ± 9.514.1
[[File:Singh 60d.svgx130pxclass=skin-invert-image]]*S*-60d2β,3β1050 ± 4588.1 ± 2.827600 ± 11000.08
[[File:Singh 60e.svgx115pxclass=skin-invert-image]]*S*-60e2α,3β1500 ± 74447 ± 472916 ± 19500.3
[[File:Singh 60f.svgx195pxclass=skin-invert-image]]*S*-60f2β,3α298 ± 17178 ± 1312400 ± 7200.6

Carboxamides

File:RTI-183 structure.png File:RTI-229 structure.png File:RTI-227 structure.png

Structure
[[File:Phenyltropane 27-29.svgx100pxclass=skin-invert-image]]X2 Position8DA
[3H]WIN 35428
(IC50 nM)NE
[3H]nisoxetine5-HT
[3H]paroxetine
(IC50 nM)Selectivity
5-HTT/DATSelectivity
NET/DAT
[[File:Phenyltropane 27b.svgx100pxclass=skin-invert-image]]RTI-106
*27b*ClCON(H)Meβ,βNMe12.4 ± 1.171584 ± 621313 ± 46
[[File:Phenyltropane 27a.svgx100pxclass=skin-invert-image]]RTI-118
*27a*ClCONH2β,βNMe11.5 ± 1.64270 ± 3591621 ± 110
[[File:Phenyltropane 29d.svgx100pxclass=skin-invert-image]]RTI-222
*29d*Memorpholinylβ,βNMe11.7 ± 0.8723601 ± 1156100K
[[File:Phenyltropane 27e.svgx100pxclass=skin-invert-image]]RTI-129
*27e*ClCONMe2β,βNMe1.38 ± 0.1942 ± 481079 ± 102
[[File:Phenyltropane 27d.svgx100pxclass=skin-invert-image]]RTI-146
*27d*ClCONHCH2OHβ,βNMe2.05 ± 0.23144 ± 397.8 ± 10
[[File:Phenyltropane 27i.svgx100pxclass=skin-invert-image]]RTI-147
*27i*ClCON(CH2)4β,βNMe1.38 ± 0.033,950 ± 7212400 ± 1207
[[File:RTI-156.svgx100pxclass=skin-invert-image]]RTI-156ClCON(CH2)5β,βNMe6.6158323468
[[File:RTI-170.svgx100pxclass=skin-invert-image]]RTI-170ClCON(H)CH2C≡CHβ,βNMe16.518394827
[[File:RTI-172.svgx100pxclass=skin-invert-image]]RTI-172ClCON(H)NH2β,βNMe44.139143815
[[File:RTI-174.svgx130pxclass=skin-invert-image]]RTI-174ClCONHCOMeβ,βNMe15843K125K
[[File:RTI-182.svgx160pxclass=skin-invert-image]]RTI-182ClCONHCH2COPhβ,βNMe7.791722827
[[File:Phenyltropane 27g.svgx110pxclass=skin-invert-image]]RTI-183✲
*27 g*ClCON(OMe)Meβ,βNMe0.85 ± 0.06549 ± 18.5724 ± 94
[[File:Phenyltropane 29c.svgx110pxclass=skin-invert-image]]RTI-186
*29c*MeCON(OMe)Meβ,βNMe2.55 ± 0.43422 ± 263402 ± 353
[[File:Phenyltropane 27h.svgx100pxclass=skin-invert-image]]RTI-198
*27h*ClCON(CH2)3β,βNMe6.57 ± 0.67990 ± 4.8814 ± 57
[[File:Phenyltropane 27c.svgx100pxclass=skin-invert-image]]RTI-196
*27c*ClCONHOMeβ,βNMe10.7 ± 1.259907 ± 63243700 ± 1960
[[File:RTI-201.svgx160pxclass=skin-invert-image]]RTI-201ClCONHNHCOPhβ,βNMe91.820K48K
[[File:Phenyltropane 27j.svgx110pxclass=skin-invert-image]]RTI-208
*27j*ClCONO(CH2)3β,βNMe1.47 ± 0.131083 ± 762470 ± 56
[[File:Phenyltropane 27l.svgx110pxclass=skin-invert-image]]RTI-214
*27l*ClCON(-CH2CH2-)2Oβ,βNMe2.90 ± 0.38545 ± 20688769 ± 1855
[[File:Phenyltropane 27f.svgx110pxclass=skin-invert-image]]RTI-215
*27f*ClCONEt2β,βNMe5.48 ± 0.195532 ± 2999433 ± 770
[[File:RTI-217.svgx150pxclass=skin-invert-image]]RTI-217ClCONH(*m*-C6H4OH)β,βNMe4.7830K16K
[[File:RTI-218.svgx100pxclass=skin-invert-image]]RTI-218✲ClCON(Me)OMeβ,βNMe1.195201911
[[File:Phenyltropane 27m.svgx150pxclass=skin-invert-image]]RTI-226
*27 m*ClCONMePhβ,βNMe45.5 ± 32202 ± 49523610 ± 2128
[[File:RTI-227.svgx100pxclass=skin-invert-image]]RTI-227ICONO(CH2)3β,βNMe0.75446230
[[File:Phenyltropane 28a.svgx100pxclass=skin-invert-image]]RTI-229
*28a*ICON(CH2)4β,βNMe0.37 ± 0.04991 ± 211728 ± 39
[[File:Phenyltropane 27k.svgx100pxclass=skin-invert-image]]*27k*6.95 ± 1.211752 ± 2023470 ± 226
[[File:Phenyltropane 28b.svgx100pxclass=skin-invert-image]]*28b*1.08 ± 0.15103 ± 6.273.9 ± 8.1
[[File:Phenyltropane 28c.svgx110pxclass=skin-invert-image]]*28c*0.75 ± 0.02357 ± 42130 ± 15.8
[[File:Phenyltropane 29a.svgx100pxclass=skin-invert-image]]*29a*41.8 ± 2.454398 ± 2716371 ± 374
[[File:Phenyltropane 29b.svgx110pxclass=skin-invert-image]]*29b*24.7 ± 1.936222 ± 72933928 ± 2192

✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.

CompoundShort Name
(S. Singh)RXIC50 (nM)
DAT
[3H]WIN 35428IC50 (nM)
5-HTT
[3H]ParoxetineIC50 (nM)
NET
[3H]NisoxetineSelectivity
5-HTT/DATSelectivity
NET/DAT
[[File:Phenyltropane 27-29.svgx100pxclass=skin-invert-image]]
29aNH2CH341.8 ± 2.456371 ± 3744398 ± 271152105
29bN(CH2CH3)2CH324.7 ± 1.9333928 ± 21926222 ± 7291374252
29c
RTI-186N(OCH3)CH3CH32.55 ± 0.433402 ± 353422 ± 261334165
29d
RTI-2224-morpholineCH311.7 ± 0.8710000023601 ± 115685472017

Carboxamide linked phenyltropanes dimers

File:Phenyltropane para chloro dimer.svg File:Phenyltropane para methyl dimer.svg File:PhenyltropaneDimerC2Benzenelink.svg File:PhenyltropaneDimerC2amide.svg File:PhenyltropaneDimer.svg

Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo.

Heterocycles

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize to the energetically more favorable trans configuration. This can happen to cocaine also.

Atomic positions A—C<br />(compound model '''34''')

Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.

To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔVmin(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔVmin(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.

In contrast to this trend, it is understood that an increasingly negative ΔVmin is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.

3-Substituted-isoxazol-5-yl

Code
*(S.S. #)*XRDANE5HT
RTI-165Cl3-methylisoxazol-5-yl0.59181572
RTI-171Me3-methylisoxazol-5-yl0.932543818
RTI-180I3-methylisoxazol-5-yl0.7367.936.4
RTI-177 β-CPPIT
*32g*Cl3-phenylisoxazol-5-yl1.28 ± 0.18504 ± 292420 ± 136
RTI-176Me3-phenylisoxazol-5-yl1.583985110
RTI-181I3-phenylisoxazol-5-yl2.57868100
RTI-184Hmethyl43.3—6208
RTI-185HPh285—12K
RTI-334Cl3-ethylisoxazol-5-yl0.501203086
RTI-335Clisopropyl1.199542318
RTI-336Cl3-(4-methylphenyl)isoxazol-5-yl4.0917145741
RTI-337Cl3-t-butyl-isoxazol-5-yl7.31632137K
RTI-345Cl*p*-chlorophenyl6.42529076K
RTI-346Cl*p*-anisyl1.577625880
RTI-347Cl*p*-fluorophenyl1.869187257
RTI-354Me3-ethylisoxazol-5-yl1.622996400
RTI-366MeR = isopropyl4.52523 (1550)42,900 (3900)
RTI-371Me*p*-chlorophenyl8.74100K (60,200)100K (9090)
RTI-386Me*p*-anisyl3.93756 (450)4027 (380)
RTI-387Me*p*-fluorophenyl6.45917 (546)100K (9400)

3-Substituted-1,2,4-oxadiazole

File:RTI-130 structure.png File:RTI-126.png

StructureCode
(*Singh's #*)XRDAT (IC50 *nM*)
displacement of WIN 35428NET (IC50 *nM*)
nisoxetine5-HTT (IC50 *nM*)
paroxetine
[[File:RTI-87.svg160pxclass=skin-invert-image]]ααRTI-87H3-methyl-1,2,4-oxadiazole20436K30K
[[File:RTI-119.svg160pxclass=skin-invert-image]]βαRTI-119H3-methyl-1,2,4-oxadiazole1677K41K
[[File:RTI-124.svg160pxclass=skin-invert-image]]αβRTI-124H3-methyl-1,2,4-oxadiazole102871K33K
[[File:Phenyltropane Singh 32a.svg170pxclass=skin-invert-image]]RTI-125
*(32a)*Cl3-methyl-1,2,4-oxadiazole4.05 ± 0.57363 ± 362584 ± 800
[[File:Phenyltropane Singh 31.svg145pxclass=skin-invert-image]]5935953}}
*(31)*H3-methyl-1,2,4-oxadiazole100 ± 67876 ± 5513824 ± 420
[[File:Phenyltropane Singh 32c.svg170pxclass=skin-invert-image]]RTI-130
*(32c)*Cl3-phenyl-1,2,4-oxadiazole1.62 ± 0.02245 ± 13195 ± 5
[[File:Phenyltropane Singh 32d.svg170pxclass=skin-invert-image]]RTI-141
*(32d)*Cl3-(*p*-anisyl)-1,2,4-oxadiazole1.81 ± 0.19835 ± 8337 ± 40
[[File:Phenyltropane Singh 32e.svg170pxclass=skin-invert-image]]RTI-143
*(32e)*Cl3-(*p*-chlorophenyl)-1,2,4-oxadiazole4.06 ± 0.2240270 ± 180
(4069)404 ± 56
[[File:Phenyltropane Singh 32f.svg170pxclass=skin-invert-image]]RTI-144
*(32f)*Cl3-(*p*-bromophenyl)-1,2,4-oxadiazole3.44 ± 0.361825 ± 170106 ± 10
[[File:Phenyltropane Singh 33.svg170pxclass=skin-invert-image]]βRTI-151
*(33)*Me3-phenyl-1,2,4-oxadiazole2.33 ± 0.2660 ± 21074 ± 130
[[File:RTI-152.svg160pxclass=skin-invert-image]]αRTI-152Me3-phenyl-1,2,4-oxadiazole494—1995
[[File:Phenyltropane Singh 32b.svg170pxclass=skin-invert-image]]RTI-154
*(32b)*Cl3-isopropyl-1,2,4-oxadiazole6.00 ± 0.55135 ± 133460 ± 250
[[File:RTI-155.svg160pxclass=skin-invert-image]]RTI-155Cl3-cyclopropyl-1,2,4-oxadiazole3.411774362
StructureCodeX2 GroupDAT (IC50 *nM*)
displacement of WIN 35428NET (IC50 *nM*)
displacement of nisoxetine5-HTT (IC50 *nM*)
displacement of paroxetineSelectivity
5-HTT/DATSelectivity
NET/DAT
[[File:RTI-157.svg150pxclass=skin-invert-image]]RTI-157Metetrazole155737K43K
[[File:RTI-163.svg170pxclass=skin-invert-image]]RTI-163Cltetrazole911—5456
[[File:RTI-178.svg170pxclass=skin-invert-image]]RTI-178Me5-phenyl-oxazol-2-yl35.46771699
[[File:RTI-188.svg170pxclass=skin-invert-image]]RTI-188Cl5-phenyl-1,3,4-oxadiazol-2-yl12.69303304
[[File:Phenyltropane Singh 32i.svg170pxclass=skin-invert-image]]RTI-189
(*32i*)Cl5-phenyl-oxazol-2-yl19.7 ± 1.98496 ± 421120 ± 10756.825.5
[[File:RTI-194.svg170pxclass=skin-invert-image]]RTI-194Me5-methyl-1,3,4-oxadiazol-2-yl4.452534885
[[File:RTI-195.svg170pxclass=skin-invert-image]]RTI-195Me5-phenyl-1,3,4-oxadiazol-2-yl47.5131022,000
[[File:RTI-199.svg170pxclass=skin-invert-image]]RTI-199Me5-phenyl-1,3,4-thiadiazol-2-yl35.924,00051,000
[[File:RTI-200.svg170pxclass=skin-invert-image]]RTI-200Cl5-phenyl-1,3,4-thiadiazol-2-yl15.3414218,000
[[File:RTI-202.svg170pxclass=skin-invert-image]]RTI-202Clbenzothiazol-2-yl1.374031119
[[File:RTI-219.svg170pxclass=skin-invert-image]]RTI-219Cl5-phenylthiazol-2-yl5.71851610,342
RTI-262Cl188.2 ± 5.01595.25 ± 57385207 ± 48831628
[[File:RTI-370.svg170pxclass=skin-invert-image]]RTI-370Me3-(*p*-cresyl)isoxazol-5-yl8.746980100K
[[File:RTI-371.svg170pxclass=skin-invert-image]]RTI-371Cl3-(*p*-chlorophenyl)isoxazol-5-yl13100K100K
[[File:RTI-436-2.svg170pxclass=skin-invert-image]]RTI-436Melast1 = Carrollfirst1 = F.last2 = Howardfirst2 = J.last3 = Howellfirst3 = L.last4 = Foxfirst4 = B.last5 = Kuharfirst5 = M.title = Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abusejournal = The AAPS Journalvolume = 8issue = 1pages = E196–E203year = 2006pmid = 16584128doi = 10.1208/aapsj080124pmc = 2751440}}3.091960 (1181)335 (31)
[[File:RTI-470.svg170pxclass=skin-invert-image]]RTI-470Cl*o*-Cl-benzothiazol-2-yl0.0941590 (994)1080 (98)
[[File:RTI-451.svg170pxclass=skin-invert-image]]RTI-451Mebenzothiazol-2-yl1.53476 (287)7120 (647)
[[File:Phenyltropane Singh 32g.svg170pxclass=skin-invert-image]]*32g*1.28 ± 0.18504 ± 292420 ± 1361891394
[[File:Phenyltropane Singh 32h.svg170pxclass=skin-invert-image]]*32h*12.6 ± 10.3929 ± 88330 ± 19626273.7
5,935,953}} (1999).

N.B There are some alternative ways of making the tetrazole ring however; Cf. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (cf. Irbesartan).

Acyl (C2-propanoyl)

File:WF-23.svg| File:WF-31.svg| File:WF-11.svg| File:WF-33.svg| File:3ß-(5-Indolyl)-8-azabicyclo(3.2.1)octanes.png|Indolyl cf. the Tamagnan series of phenyltropanes for examples with a methylene unit spacer breaking up the indole.

#
(*#*)XY2 Positionconfig8DA5-HTNE
WF-23
(*39n*)β-naphthylC(O)Etβ,βNMe0.1150.394No data
[WF-31](2-propanoyl-3-4-isopropylphenyl-tropane) PIT-PriHC.O.Etβ,βNMe61554.5No data
[WF-11](2b-propanoyl-3b-4-tolyl-tropane)*✲* PTT
(*39e*)MeH-C.O.Etβ,βNMe8.2131No data
WF-25
(*39a*)HH-C.O.Etβ,βNMe48.31005No data
[WF-33](2a-propanoyl-3b-2-6-methoxynaphthyl-tropane)6-MeoBNC(O)Etα,βNMe0.132.24No data
*✲*Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine *i.e.* tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration)
StructureS. Singh's
alphanumeric
assignation
(name)R1R2DAT5-HTTSelectivity
cocaine173 ± 19——
Troparil
11a
(WIN 35065–2)98.8 ± 12.2——
[[File:Singh 39a.svgx100pxclass=skin-invert-image]]WF-25
39aC2H5C6H548.3 ± 2.81005 ± 11220.8
[[File:Singh 39b.svgx100pxclass=skin-invert-image]]39bCH3C6H5114 ± 221364 ± 61612.0
[[File:Singh 39c.svgx100pxclass=skin-invert-image]]39cC2H5C6H4-4-F15.3 ± 2.8630 ± 6741.2
[[File:Singh 39d.svgx100pxclass=skin-invert-image]]39dCH3C6H4-4-F70.8 ± 13857 ± 18712.1
[[File:Singh 39e.svgx100pxclass=skin-invert-image]]WF-11
39eC2H5C6H4-4-CH38.2 ± 1.6131 ± 116.0
(+)-39eC2H5C6H4-4-CH34.21 ± 0.0574 ± 1217.6
(-)-39eC2H5C6H4-4-CH31337 ± 12210000—
[[File:Singh 39f.svgx100pxclass=skin-invert-image]]39fCH3C6H4-4-CH39.8 ± 0.5122 ± 2212.4
[[File:Singh 39g.svgx100pxclass=skin-invert-image]]39gCH3C6H4-4-C2H5152 ± 2478.2 ± 220.5
[[File:Singh 39h.svgx100pxclass=skin-invert-image]]39hC2H5C6H4-4-CH(CH3)2436 ± 4135.8 ± 4.40.08
[[File:Singh 39i.svgx100pxclass=skin-invert-image]]39iC2H5C6H4-4-C(CH3)32120 ± 6301771 ± 4740.8
[[File:Singh 39j.svgx100pxclass=skin-invert-image]]39jC2H5C6H4-4-C6H52.29 ± 1.084.31 ± 0.011.9
[[File:Singh 39k.svgx130pxclass=skin-invert-image]]39kC2H5C6H4-2-CH31287 ± 3227100007.8
[[File:Singh 39l.svgx130pxclass=skin-invert-image]]39lC2H51-naphthyl5.43 ± 1.2720.9 ± 2.93.8
[[File:Singh 39m.svgx130pxclass=skin-invert-image]]39mCH31-naphthyl10.1 ± 2.225.6 ± 5.12.5
[[File:Singh 39n.svgx100pxclass=skin-invert-image]]WF-23
39nC2H52-naphthyl0.115 ± 0.0210.394 ± 0.0743.5
[[File:Singh 39o.svgx100pxclass=skin-invert-image]]39oCH32-naphthyl0.28 ± 0.111.06 ± 0.363.8
[[File:Singh 39p.svgx100pxclass=skin-invert-image]]39pC2H5C6H4-4-CH(C2H5)2270 ± 38540 ± 512.0
[[File:Singh 39q.svgx100pxclass=skin-invert-image]]39qC2H5C6H4-4-C6H11320 ± 5597 ± 120.30
[[File:Singh 39r.svgx100pxclass=skin-invert-image]]39rC2H5C6H4-4-CH=CH20.90 ± 0.343.2 ± 1.33.5
[[File:Singh 39s.svgx100pxclass=skin-invert-image]]39sC2H5C6H4-4-C(=CH2)CH37.2 ± 2.10.82 ± 0.380.1

2β-Acyl-3β-naphthyl substituted

StructureShort Assignation
(Numeric code, Davies UB)
*S. Singh*RDAT
[125H]RTI-55**ɑ**
IC50 nMSERT
[3H]paroxetine**b**
*Ki* nMNET
[3H]nisoxetine**c**
*Ki* nMpotency ratio
SERT/DATpotency ratio
SERT/NET
[[File:WF-11.svgclass=skin-invert-image]]WF-11
(6)4′-Me8.2 ± 1.6131 ± 1065 ± 9.20.060.5
[[File:WF-31.svgclass=skin-invert-image]]WF-31
(7)4′-iPr436 ± 4136 ± 410,00012250
[[File:WF-23.svgclass=skin-invert-image]]WF-23
(8)2-naphthalene0.12 ± 0.020.39 ± 0.072.9 ± 0.50.37
[[File:Davies 9a.svgx150pxclass=skin-invert-image]]2β-acyl-3β-1-naphthalene
(9a)4′-H5.3 ± 1.321 ± 2.949 ± 100.318
[[File:Davies 9b.svgx150pxclass=skin-invert-image]](9b)4′-Me25.1 ± 0.58.99 ± 1.70163 ± 36318
[[File:Davies 9c.svgx150pxclass=skin-invert-image]](9c)4′-Et75.1 ± 11.9175 ± 254769 ± 6880.727
[[File:Davies 9d.svgx150pxclass=skin-invert-image]](9d)4′-iPr225 ± 36136 ± 6410,000273.5
[[File:Davies 10a.svgx110pxclass=skin-invert-image]](10a)6′-Et0.15 ± 0.040.38 ± 0.1927.7 ± 9.60.474
[[File:Davies 10b.svgx110pxclass=skin-invert-image]](10b)6′-iPr0.39 ± 0.041.97 ± 0.33no data0.2—
[[File:Davies 10c.svgx110pxclass=skin-invert-image]](10c**e**)6′- OMe0.13 ± 0.042.24 ± 0.34no data0.05—
[[File:Davies 10d.svgx110pxclass=skin-invert-image]](10d)5′-Et, 6′-OMe30.8 ± 6.67.55 ± 1.573362 ± 1484.1445
[[File:Davies 10e.svgx110pxclass=skin-invert-image]](10e)5′-C(Me)=CH2, 6′-OMe45.0 ± 3.788.0 ± 13.32334 ± 3780.526.5
[[File:Davies 10f.svgx110pxclass=skin-invert-image]](10f)6′-I0.35 ± 0.070.37 ± 0.02no data1.0—
[[File:Davies 10g.svgx120pxclass=skin-invert-image]](10g)7′-I0.45 ± 0.050.47 ± 0.02no data0.5**d**—
[[File:Davies 10h.svgx110pxclass=skin-invert-image]](10h)5′-NO2, 6′-OMe148 ± 5015 ± 1.6no data10—
[[File:Davies 10i.svgx110pxclass=skin-invert-image]](10i)5′-I, 6′-OMe1.31 ± 0.332.27 ± 0.31781 ± 1810.6344
[[File:Davies 10j.svgx110pxclass=skin-invert-image]](10j)5′-COMe, 6′-OMe12.6 ± 3.815.8 ± 1.65498 ± 240.832
[[File:Davies 11a.svgx145pxclass=skin-invert-image]](11a)2β-COCH3, 1-naphthyl10 ± 2.226 ± 5.1165 ± 400.46.3
[[File:Davies 11b.svgx135pxclass=skin-invert-image]](11b)2α-COCH3, 1-naphthyl97 ± 21217 ± 55no data0.45—
[[File:Davies 11c.svgx120pxclass=skin-invert-image]](11c)2α-COCH2CH3, 2-naphthyl2.51 ± 0.8216.4 ± 2.068.0 ± 10.80.154.1
[[File:Davies 11d.svgx110pxclass=skin-invert-image]](11d)2β-COCH3, 2-naphthyl1.27 ± 0.151.06 ± 0.364.9 ± 1.21.24.6
[[File:Davies 11e.svgx110pxclass=skin-invert-image]](11e)2β-COCH(CH3)2, 2-naphthyl0.25 ± 0.082.08 ± 0.8037.6 ± 10.50.1218.1
[[File:Davies 11f.svgx110pxclass=skin-invert-image]](11f)
*79a*2β-COCH2CH3, 2-naphthyl, *N*8-demethyl0.03 ± 0.010.23 ± 0.072.05 ± 0.90.138.9

Ester reduction

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.

CodeX2 Positionconfig8DA5-HTNE
RTI-100F-CH2OHβ,βNMe474741no data
RTI-101I-CH2OHβ,βNMe2.226no data
RTI-99Br-CH2OHβ,βNMe1.4951no data
RTI-93Cl-CH2OHβ,βNMe1.5320443.8
RTI-105Cl-CH2OAcβ,βNMe1.60143127
RTI-123Cl-CH2OBzβ,βNMe1.783.53393
RTI-145Cl-CH2OCO2Meβ,βNMe9.602.931.48

2-Alkane/Alkene

StructureSingh's #RXDAT
mazindol displacementDA uptake5-HT UptakeSelectivity
DA uptake/DAT binding
[[File:WIN 35,065-2.svg160pxrightclass=skin-invert-image]]11a
WIN 35062-289.453.71860.6
[[File:Chlorophenyltropane.png160pxleftclass=skin-invert-image]]11c0.83 ± 00.728.5 ± 0.9—34.3
[[File:RTI-32 structure.png160pxleftclass=skin-invert-image]]11f5.766.9223.21.2
[[File:Cocaine analog 41a.svg160pxleftclass=skin-invert-image]]41a(CH2)2CH3H12.26.8986.80.6
[[File:Cocaine analog 41b.svg190pxleftclass=skin-invert-image]]41b(CH2)3C6H5H16 ± 2*a*43 ± 13*b*—2.7
[[File:Cocaine analog 42.svg160pxleftclass=skin-invert-image]]42(CH2)2CH3F5.281.9921.70.4
[[File:Cocaine analog 43a.svg160pxleftclass=skin-invert-image]]43aCH=CH2Cl0.59 ± 0.152.47 ± 0.5—4.2
[[File:Cocaine analog 43b.svg160pxleftclass=skin-invert-image]]43bE-CH=CHClCl0.42 ± 0.041.13 ± 0.27—2.7
[[File:Cocaine analog 43c.svg160pxleftclass=skin-invert-image]]43cZ-CH=CHClCl0.22 ± 0.020.88 ± 0.05—4.0
[[File:Cocaine analog 43d.svg160pxleftclass=skin-invert-image]]43dE-CH=CHC6H5Cl0.31 ± 0.040.66 ± 0.01—2.1
[[File:Cocaine analog 43e.svg160pxleftclass=skin-invert-image]]43eZ-CH=CHC6H5Cl0.14 ± 0.070.31 ± 0.09—2.2
[[File:Cocaine analog 43f.svg160pxleftclass=skin-invert-image]]43fCH2CH3Cl2.17 ± 0.202.35 ± 0.52—1.1
[[File:Cocaine analog 43g.svg160pxleftclass=skin-invert-image]]43 g(CH2)2CH3Cl0.94 ± 0.081.08 ± 0.05—1.1
[[File:Cocaine analog 43h.svg160pxleftclass=skin-invert-image]]43h(CH2)3CH3Cl1.21 ± 0.180.84 ± 0.05—0.7
[[File:Cocaine analog 43i.svg160pxleftclass=skin-invert-image]]43i(CH2)5CH3Cl156 ± 15271 ± 3—1.7
[[File:Cocaine analog 43j.svg160pxleftclass=skin-invert-image]]43j(CH2)2C6H5Cl1.43 ± 0.031.54 ± 0.08—1.0
[[File:Cocaine analog 44a.svg160pxleftclass=skin-invert-image]]44a(CH2)2CH3CH31.571.1010.30.7
[[File:Cocaine analog 44b.svg160pxleftclass=skin-invert-image]]44b(CH2)3CH3CH31.821.3115.10.7
[[File:Cocaine analog 45.svg110pxleftclass=skin-invert-image]]45(CH2)2CH3H74.930.23890.4
[[File:Cocaine analog 46.svg110pxleftclass=skin-invert-image]]46(CH2)2CH3F21.112.199.60.6
[[File:Cocaine analog 47a.svg110pxleftclass=skin-invert-image]]47a(CH2)2CH3CH38.9111.850.11.3
[[File:Cocaine analog 47b.svg120pxleftclass=skin-invert-image]]47b(CH2)3CH3CH311.410.151.00.9

a**Ki value for displacement of WIN 35428.

bIC50 value.

Irreversible covalent (''cf.'' ionic) C2 ligands

Irreversible (phenylisothiocyanate) binding ligand ({{Cite journal

C2 Acyl, N8 phenylisothiocyanate

HD-205 (Murthy et al., 2007)

Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

Benztropine based (C2-position hetero-substituted) phenyltropanes

StructureCompoundRXY[3H]WIN 35,428
@ DAT
*Ki* (nM)[3H]Citalopram
@ SERT
K*i* (nM)[3H]Nisoxetine
@ NET
K*i* (nM)[3H]Pirenzepine
@ M1
K*i* (nM)
[[File:Benztropine phenyltropane 9.svg200pxclass=skin-invert-image]]
9aCH3HH34 ± 2121 ± 19684 ± 10010,600 ± 1,100
9bFHH49 ± 12———
9cClHH52 ± 2.1147 ± 81,190 ± 7211,000 ± 1,290
9dCH3ClH80 ± 9443 ± 604,400 ± 23831,600 ± 4,300
9eFClH112 ± 11———
9fClClH76 ± 7462 ± 362,056 ± 23639,900 ± 5,050
9gCH3FF62 ± 7233 ± 241,830 ± 17715,500 ± 1,400
9hFFF63 ± 13———
9iClFF99 ± 18245 ± 162,890 ± 22216,300 ± 1,300
[[File:Benztropine phenyltropane 10.svg200pxclass=skin-invert-image]]
10aCH3HH455 ± 36530 ± 722,609 ± 19512,600 ± 1,790
10cClHH478 ± 72408 ± 163,998 ± 25611,500 ± 1,720
10dCH3ClH937 ± 841,001 ± 10922,500 ± 2,82118,200 ± 2,600
10fClClH553 ± 1061,293 ± 405,600 ± 1839,600 ± 600
10gCH3FF690 ± 76786 ± 6716,000 ± 6379,700 ± 900
10iClFF250 ± 40724 ± 10052,300 ± 13,6009,930 ± 1,090
[[File:Benztropine phenyltropane 12.svg200pxclass=skin-invert-image]]
12aHHH139 ± 1561 ± 9207 ± 307,970 ± 631
12bHClH261 ± 1945 ± 3—24,600 ± 2,930
12cHFF60 ± 7———

F&B series (Biotin side-chains etc.)

One patent claims a series of compounds with biotin-related sidechains are pesticides.

Images of the biotin C2 side-chained phenyltropanes, click to
StructureCode*para*-XC2-Tropane PositionconfigDANE5-HT
[[File:Phenyltropane F1 (2-H).svgx150pxclass=skin-invert-image]]—HF1β,β———
[[File:Phenyltropane F1 (2-Me).svgx140pxclass=skin-invert-image]]RTI-224MeF1cβ,β4.49—155.6
[[File:Phenyltropane F2.svgx160pxclass=skin-invert-image]]RTI-233MeF2β,β4.3851673.6
[[File:Phenyltropane F3 (N8).svgx160pxclass=skin-invert-image]]RTI-235MeF3dβ,β1.7540272.4
[[File:Phenyltropane F3 (nortropane).svgx150pxclass=skin-invert-image]]——F3β,β———
[[File:Phenyltropane B1.svgx140pxclass=skin-invert-image]]RTI-236MeB1dβ,β1.6386.8138
[[File:Phenyltropane B2.svgx140pxclass=skin-invert-image]]RTI-237MeB2dβ,β7.27258363
[[File:Phenyltropane B3.svgx160pxclass=skin-invert-image]]RTI-244MeB3dβ,β15.6180933.7
[[File:Phenyltropane F4.svgx140pxclass=skin-invert-image]]RTI-245ClF4cβ,β77.3——
RTI-246MeF4cβ,β50.33000—
[[File:Phenyltropane F5.svgx150pxclass=skin-invert-image]]——F5β,β———
[[File:Phenyltropane F6.svgx120pxclass=skin-invert-image]]RTI-248ClF6cβ,β9.7346746.96
[[File:Phenyltropane F1 (3-Ar-4-Cl).svgx140pxclass=skin-invert-image]]RTI-249ClF1cβ,β8.32502381.6
RTI-266MeF2β,β4.80836842
RTI-267MeF7 wrongβ,β2.52324455
[[File:Phenyltropane F7.svgx210pxclass=skin-invert-image]]RTI-268MeF7 rightβ,β3.891014382
[[File:Phenyltropane F8.svgx220pxclass=skin-invert-image]]RTI-269MeF8β,β5.55788986

Miscellany (''i.e.'' Misc./Miscellaneous) C2-substituents

StructureCodeX2 Positionconfig8DA5-HTNE
[[File:RTI-102.svg170pxclass=skin-invert-image]]RTI-102ICO2Hβ,βNMe474192843,400
[[File:RTI-103.svg170pxclass=skin-invert-image]]RTI-103BrCO2Hβ,βNMe278307017,400
[[File:RTI-104.svg170pxclass=skin-invert-image]]RTI-104FCO2Hβ,βNMe2744100K100K
[[File:RTI-108.svg170pxclass=skin-invert-image]]RTI-108Cl-CH2Clβ,βNMe2.6498129.8
[[File:RTI-241.svg170pxclass=skin-invert-image]]RTI-241Me-CH2CO2Meβ,βNMe1.02619124
[[File:RTI-139.svg170pxclass=skin-invert-image]]RTI-139Cl-CH3β,βNMe1.678557
[[File:RTI-161.svg170pxclass=skin-invert-image]]RTI-161Cl-C≡Nβ,βNMe13.118872516
[[File:RTI-230.svg170pxclass=skin-invert-image]]RTI-230ClH3C–C=CH2β,βNMe1.2857141
[[File:RTI-240.svg170pxclass=skin-invert-image]]RTI-240Cl-CHMe2β,βNMe1.3838.484.5
[[File:RTI-145.svg170pxclass=skin-invert-image]]RTI-145Cl-CH2OCO2Meβ,βNMe9.602,9321,478
[[File:RTI-158.svg170pxclass=skin-invert-image]]RTI-158Me-C≡Nβ,βNMe5750951624
[[File:RTI-131.svg170pxclass=skin-invert-image]]RTI-131Me-CH2NH2β,βNMe10.5855120
[[File:RTI-164.svg170pxclass=skin-invert-image]]RTI-164Me-CH2NHMeβ,βNMe13.62246280
[[File:RTI-132.svg170pxclass=skin-invert-image]]RTI-132Me-CH2NMe2β,βNMe3.48206137
[[File:RTI-239.svg170pxclass=skin-invert-image]]RTI-239Me-CHMe2β,βNMe0.6111435.6
[[File:RTI-338.svg180pxclass=skin-invert-image]]RTI-338Et-CO2CH2Phβ,βNMe11047.413366
[[File:RTI-348.svg150pxclass=skin-invert-image]]RTI-348H-Phβ,βNMe28.234,0002670

C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes)

Aryl-Tropenes

Test compoundDA-uptake IC50(μM)NA-uptake IC50(μM)5-HT-uptake IC50(μM)
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene0.260.0280.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene0.0580.0130.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene0.0340.0180.00023
number=9713770}}
Test CompoundDA uptake IC50(μM)NE uptake IC50(μM)5-HT uptake IC50(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene0.0790.0260.0047
Test CompoundDA uptake IC50(μM)NE uptake IC50(μM)5-HT uptake IC50(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene184.90.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene1.50.50.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene22.008.000.0036

Enantioselective nonstandard configurations (non-2β-,3β-)

β,α Stereochemistry

**Structure** [[File:Phenyltropanes 20a-e.svg100pxclass=skin-invert-image]]**Compound
(RTI #)**
*(S. Singh's #)***X****2 Group****config****8****DAT** IC50 (*nM*)
[3H]WIN 35428**5-HTT** IC50 (*nM*)
[3H]paroxetine**NET** IC50 (*nM*)
[3H]nisoxetineselectivity
5-HTT/DATselectivity
NET/DAT
[[File:Phenyltropane 20a.svg100pxclass=skin-invert-image]]RTI-140
*20a*HCO2Meβ,αNMe101 ± 165,701 ± 7212,076 ± 28556.420.6
[[File:RTI-352.svg100pxclass=skin-invert-image]]RTI-352**ɑ**
*20d*ICO2Meβ,αNMe2.86 ± 0.1664.9 ± 1.9752.4 ± 4.922.818.4
[[File:RTI-549.svg100pxclass=skin-invert-image]]RTI-549BrCO2Meβ,αNMe—————
[[File:RTI-319.svg100pxclass=skin-invert-image]]RTI-319**b**3α-2-naphthylCO2Meβ,αNMe1.1 ± 0.0911.4 ± 1.370.2 ± 6.28——
[[File:Phenyltropane 20b.svg100pxclass=skin-invert-image]]RTI-286**c**
*20b*FCO2Meβ,αNMe21 ± 0.575062 ± 4851231 ± 9124158.6
[[File:RTI-274.svg140pxclass=skin-invert-image]]RTI-274**d**FCH2O(3′,4′-MD-phenyl)β,αNH3.965.6214.4——
[[File:RTI-287.svg100pxclass=skin-invert-image]]RTI-287EtCO2Meβ,αNMe327168717,819——
[[File:Phenyltropane 20c.svg100pxclass=skin-invert-image]]*20c*ClCO2Meβ,αNMe2.4 ± 0.2998 ± 12060.1 ± 2.441625.0
[[File:Phenyltropane 20e.svg100pxclass=skin-invert-image]]*20e*MeCO2Meβ,αNMe10.2 ± 0.084250 ± 422275 ± 2441727.0
[[File:RTI-319 alt.svg120pxclass=skin-invert-image]]BnCO2Meβ,αNMe—————

α,β Stereochemistry

File:Brasofensine.svg File:Tesofensine chemical structure.png File:NStwothreefivenine.png

CompoundDA (μM)M.E.D. (mg/kg)Dose (mg/kg)ActivityActivity
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane0.395000
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane0.112500
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane0.0160.2550++++

di-chloro; ''para''- & ''meta''- in tandem (α,β configured phenyltropanes)

CompoundX2 Groupconfig8DA5-HTNE
BrasofensineCl2methyl aldoximeα,βNMe———
TesofensineCl2ethoxymethylα,βNMe65111.7
NS-2359 (GSK-372,475)Cl2Methoxymethylα,βNH———

fumaric acid salts (of α,β configured phenyltropanes)

Test CompoundDA uptake IC50(μM)NE uptake IC50(μM)5-HT uptake IC50(μM)
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0620.0350.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0620.150.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.100.0480.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0880.0510.013

Arene equivalent alterations

''η''6-3β-(transition metal complexed phenyl)tropanes

year=2002}}</ref>

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule. (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.).

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity Ki values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.

The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)3 whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.

Diagram indicating the triflate, in bracket, superimposed as a direct connection between the ''η''<sup>6</sup> benzene containing its transition metal fixed upon the ''η''<sup>5</sup>-penta-methyl (five-methyls) cyclopenta-dienyl (five sided ring) alongside the benzene in three dimension.
StructureCompound #
(S. Singh)
**Systematic name***Ki* (*nM*)**ɑ**IC50 (*nM*)selectivity
binding/uptake
[[File:Cocaine analog 21a.svg250pxleftclass=skin-invert-image]]21a**c**17 ± 15**b**
224 ± 8341824.6
[[File:Cocaine analog 21b.svg310pxleft]]21b**d**2280 ± 18338901.7
Cocaine32 ± 5
388 ±22140512.6
Troparil (11a)33 ± 17
314 ± 22237311.3
  • ɑThe binding data fit a two-site model better than a one-site model
  • bThe Ki value for the one-site model was 124 ± 10 nM
  • cIUPAC: [η6-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
  • dIUPAC: [η5-(pentamethylcyclopentadienyl)]-[η6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

3-(2-thiophene) and 3-(2-furan)

7247643}}
CodeCompoundDA (μM)NE (μM)5-HT (μM)
1(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt0.300.00190.00052
2(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.360.00360.00042
3(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.310.000900.00036
4(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.920.00300.00053
5(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt0.0740.00180.00074
6(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt0.190.00160.00054

Thiophenyltropanes

Diaryl

File:Hanna et al.png|Fluoxetine homologue, also: Hanna et al. (2007) cf. the paroxetine homologue PTs File:ZIENT.png|ZIENT:

6/7-tropane position substituted

2β-carbomethoxy 6/7 substituted

StructureCompound #
(S. Singh)SubstitutionDAT (IC50 *nM*)
displacement of [H3]WIN 354285-HTT (IC50 *nM*)
[H3]CitalopramSelectivity
5-HTT/DAT
CocaineH65 ± 12--
[[File:Phenyltropane 103a.svg160pxclass=skin-invert-image]]103a3β,2β, 7-OMe
3′,4′-Cl286 ± 4.7884 ± 10010.3
[[File:Phenyltropane 103b.svg160pxclass=skin-invert-image]]103b3β,2β, 7-OH
3′,4′-Cl21.42 ± 0.0328.6 ± 7.820.1
[[File:Phenyltropane 103c.svg130pxclass=skin-invert-image]]103c3α,2β, 7-OH
3′,4′-Cl21.19 ± 0.161390 ± 561168
[[File:Phenyltropane 104a.svg160pxclass=skin-invert-image]]104a3β,2β, 6-OH
4′-Me215**ɑ**--
[[File:Phenyltropane 104b.svg160pxclass=skin-invert-image]]104b3β,2α, 6-OH
4′-Me15310**ɑ**--
[[File:Phenyltropane 104c.svg130pxclass=skin-invert-image]]104c3α,2β, 6-OH
4′-Me930**ɑ**--
[[File:Phenyltropane 104d.svg130pxclass=skin-invert-image]]104d3α,2α, 6-OH
4′-Me7860**ɑ**--
  • ɑIC50 value for displacement of [H3]mazindol. IC50 for cocaine 288 nM for displacement of [H3]mazindol

3-butyl 6/7 substituted

StructureCompound #
(S. Singh)SubstituentKi *nM*
displacement of [H3]mazindol bindingKi *nM*
[H3]DA uptakeSelectivity
uptake/binding
CocaineH270 ± 0.03400 ± 201.5
[[File:Phenyltropane 121a.svgx70pxclass=skin-invert-image]]121a7β-CN2020 ± 10710 ± 400.3
[[File:Phenyltropane 121b.svgx70pxclass=skin-invert-image]]121b6β-CN3040 ± 4806030 ± 8802.0
[[File:Phenyltropane 121c.svgx70pxclass=skin-invert-image]]121c7β-SO2Ph4010 ± 3108280 ± 13402.1
[[File:Phenyltropane 121d.svgx90pxclass=skin-invert-image]]121d6β-SO2Ph4450 ± 4308270 ± 6901.8
[[File:Phenyltropane 121e.svgx80pxclass=skin-invert-image]]121e7α-OH830 ± 40780 ± 600.9
[[File:Phenyltropane 121f.svgx130pxclass=skin-invert-image]]121fH100 ± 1061 ± 100.6
[[File:Phenyltropane 121g.svgx130pxclass=skin-invert-image]]121g7β-CN24000 ± 342032100 ± 85401.3
[[File:Phenyltropane 121h.svgx130pxclass=skin-invert-image]]121h6β-CN11300 ± 154026600 ± 33302.3
[[File:Phenyltropane 121i.svgx130pxclass=skin-invert-image]]121i7β-SO2Ph7690 ± 27707050 ± 4500.9
[[File:Phenyltropane 121j.svgx130pxclass=skin-invert-image]]121j6β-SO2Ph4190 ± 7008590 ± 13602.0
[[File:Phenyltropane 121k.svgx130pxclass=skin-invert-image]]121k7α-SO2Ph3420 ± 1100--
[[File:Phenyltropane 121l.svgx130pxclass=skin-invert-image]]121l7β-SO2Ph, 7α-F840 ± 2602520 ± 2903.0
[[File:Phenyltropane 121m.svgx130pxclass=skin-invert-image]]121m7α-F200 ± 10680 ± 103.4
[[File:Phenyltropane 121n.svgx130pxclass=skin-invert-image]]121n7β-F500 ± 10550 ± 1401.1

intermediate 6- & 7-position synthesis modified phenyltropanes

StructureCompound #
(S. Singh)Substituent WSubstituent XSubstituent YSubstituent Z
[[File:Phenyltropane 122a.svgx120pxclass=skin-invert-image]](±)-122aCNHHH
[[File:Phenyltropane 122b.svgx120pxclass=skin-invert-image]](±)-122bHHCHH
[[File:Phenyltropane 122c.svgx120pxclass=skin-invert-image]](±)-122cHCHHH
[[File:Phenyltropane 122d.svgx120pxclass=skin-invert-image]](±)-122dHHHCH
[[File:Phenyltropane 122e.svgx120pxclass=skin-invert-image]](±)-122eSO2PhHHH
[[File:Phenyltropane 122f.svgx120pxclass=skin-invert-image]](±)-122fHHSO2PhH
[[File:Phenyltropane 122g.svgx120pxclass=skin-invert-image]](±)-122gHSO2PhHH
[[File:Phenyltropane 122h.svgx120pxclass=skin-invert-image]](±)-122hSO2PhFHH
[[File:Phenyltropane 122i.svgx120pxclass=skin-invert-image]](±)-122iFSO2PhHH
[[File:Phenyltropane 122j.svgx120pxclass=skin-invert-image]](±)-122jHHSO2PhF

8-tropane (bridgehead) position modified

Nortropanes (''N''-demethylated)

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.{{Cite journal

Code
*(S.S. #)*X
*para*
DA5HTNE
RTI-142
*75b*F4.3968.618.8
RTI-98
*75d*
Nor**ɑ**-RTI-55I0.690.3611.0
RTI-110
*75c*Cl0.624.135.45
RTI-173
*75f*Et49.98.13122
RTI-279
Nor**ɑ**-RTI-280*para*-Me
*meta*-I5.98 ± 0.481.06 ± 0.1074.3 ± 3.8
RTI-305
Nor**ɑ**-RTI-360/*11y*Ethynyl1.24 ± 0.111.59 ± 0.221.8 ± 1.0
RTI-307
Nor**ɑ**-RTI-281/*11z*Propynyl6.11 ± 0.673.16 ± 0.33115.6 ± 5.1
RTI-309
Nor**ɑ**-*11t*Vinyl1.73 ± 0.052.25 ± 0.1714.9 ± 1.18
RTI-330
Nor**ɑ**-*11s*Isopropyl310.2 ± 2115.1 ± 0.97—
RTI-353*para*-Et
*meta*-I330.54 ± 17.120.69 ± 0.07148.4 ± 9.15

ɑThe N-demethylated variant of (i.e. compound code-name after dash)

*N*-Me compound code#
→
*N*-demethylated derivative
compound code #*para*-X[3H]Paroxetine[3H]WIN 35,428[3H]Nisoxetine
*11 g*→*75f*Ethyl28.4 → 8.1355 → 49.94,029 → 122
*11t*→*75i*Vinyl9.5 → 2.251.24 → 1.7378 → 14.9
*11y*→*75n*Ethynyl4.4 → 1.591.2 → 1.2483.2 → 21.8
*11r*→*75 g*1-Propyl70.4 → 2668.5 → 2123,920 → 532
*11v*→*75k**trans*-propenyl11.4 → 1.35.29 → 28.61,590 → 54
*11w*→*75l**cis*-propenyl7.09 → 1.1515 → 31.62,800 → 147
*11x*→*75 m*Allyl28.4 → 6.232.8 → 56.52,480 → 89.7
*11z*→*75o*1-Propynyl15.7 → 3.162.37 → 6.11820 → 116
*11s*→*75h**i*-Propyl191 → 15.1597 → 31075,000 → ?
*11u*→*75j*2-Propenyl3.13 → 0.614.4 → 231,330? → 144
Isomer4′3′NEDA5HT
β,βMeH60 → 7.21.7 → 0.84240 → 135
β,βFH835 → 18.815.7 → 4.4760 → 68.6
β,βClH37 → 5.451.12 → 0.6245 → 4.13
β,αMeH270 → 910.2 → 33.64250 → 500
β,αFH1200 → 9.821 → 32.65060 → 92.4
β,αClH60 → 5.412.4 → 3.1998 → 53.3
β,αFMe148 → 4.2313.7 → 9.381161 → 69.8
β,αMeF44.7 → 0.867.38 → 91150 → 97.4

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).{{Cite journal

StructureShort Name
(S. Singh)*Para*-XDAT
[3H]WIN 35428 IC50 (nM)5-HTT
[3H]Paroxetine IC50 (nM)NET
[3H]Nisoxetine IC50 (nM)Selectivity
5-HTT/DATSelectivity
NET/DAT
NorcocaineH206 ± 29127 ± 13139 ± 90.60.7
[[File:Singh 75a.svgx100pxclass=skin-invert-image]]75aH30.8 ± 2.3156 ± 884.5 ± 7.55.12.7
[[File:Singh 75b.svgx100pxclass=skin-invert-image]]75bF4.39 ± 0.2068.6 ± 2.018.8 ± 0.715.64.3
[[File:Singh 75c.svgx100pxclass=skin-invert-image]]75cCl0.62 ± 0.094.13 ± 0.625.45 ± 0.216.78.8
[[File:Singh 75d.svgx100pxclass=skin-invert-image]]75dI0.69 ± 0.20.36 ± 0.057.54 ± 3.190.510.9
[[File:Singh 75e.svgx110pxclass=skin-invert-image]]75e*para*-I
&
2β-CO2CH(CH3)21.06 ± 0.123.59 ± 0.27132 ± 53.4124
[[File:Singh 75f.svgx100pxclass=skin-invert-image]]75fC2H549.9 ± 7.38.13 ± 0.30122 ± 120.22.4
[[File:Singh 75g.svgx100pxclass=skin-invert-image]]75g*n*-C3H7212 ± 1726 ± 1.3532 ± 8.10.12.5
[[File:Singh 75h.svgx100pxclass=skin-invert-image]]75hCH(CH3)2310 ± 2115.1 ± 0.97-0.05-
[[File:Singh 75i.svgx100pxclass=skin-invert-image]]75iCH=CH21.73 ± 0.052.25 ± 0.1714.9 ± 1.181.38.6
[[File:Singh 75j.svgx100pxclass=skin-invert-image]]75jC-CH3
║
CH223 ± 0.90.6 ± 0.06144 ± 120.036.3
[[File:Singh 75k.svgx100pxclass=skin-invert-image]]75k*trans*-CH=CHCH328.6 ± 3.11.3 ± 0.154 ± 160.041.9
[[File:Singh 75l.svgx100pxclass=skin-invert-image]]75l*cis*-CH=CHCH331.6 ± 2.21.15 ± 0.1147 ± 4.30.044.6
[[File:Singh 75m.svgx100pxclass=skin-invert-image]]75mCH2CH=CH256.5 ± 566.2 ± 0.389.7 ± 9.60.11.6
[[File:Singh 75n.svgx100pxclass=skin-invert-image]]75nCH≡CH1.24 ± 0.111.59 ± 0.221.8 ± 1.01.317.6
[[File:Singh 75o.svgx100pxclass=skin-invert-image]]75oCH≡CCH36.11 ± 0.673.16 ± 0.33116 ± 5.10.519.0
[[File:Singh 75p.svgx110pxclass=skin-invert-image]]75p**ɑ**3,4-Cl20.66 ± 0.241.4**b**-2.1-

ɑThese values determined in Cynomolgus monkey caudate-putamen bThe radioligand used for 5-HTT was [3H]citalopram

Compound StructureShort Name
(S. Singh)DAT
[125I]RTI-55 IC50 (nM)5-HTT
[3H]Paroxetine *Ki* (nM)NET
[3H]Nisoxetine *Ki* (nM)Selectivity
5-HTT/DATSelectivity
NET/DAT
[[File:Singh 79a.svgx100pxclass=skin-invert-image]]79a0.07 ± 0.010.22 ± 0.162.0 ± 0.093.128.6
[[File:Singh 79b.svgx100pxclass=skin-invert-image]]79b4.7 ± 0.5819 ± 1.45.5 ± 2.04.01.2
[[File:Singh 79c.svgx100pxclass=skin-invert-image]]79c380 ± 1105.3 ± 1.03400 ± 2700.018.9
[[File:Singh 79d.svgx100pxclass=skin-invert-image]]79d190 ± 17150 ± 505100 ± 2200.826.8
[[File:Singh 79e.svgx100pxclass=skin-invert-image]]79e490 ± 12085 ± 164300 ± 11000.18.8
[[File:Singh 79f.svgx100pxclass=skin-invert-image]]79f1.5 ± 1.10.32 ± 0.0610.9 ± 1.50.27.3
[[File:Singh 79g.svgx100pxclass=skin-invert-image]]79g16 ± 4.90.11 ± 0.0294 ± 180.075.9

Paroxetine homologues

See the N-methyl paroxetine homologues cf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.

Compound StructureShort Name
(S. Singh)StereochemistryDAT
[3H]WIN 35428 IC50 (nM)5-HTT
[3H]Paroxetine IC50 (nM)NET
[3H]Nisoxetine IC50 (nM)Selectivity
5-HTT/DATSelectivity
NET/DAT
[[File:Paroxetine-2D-skeletal.svgx130pxclass=skin-invert-image]]Paroxetine-623 ± 250.28 ± 0.02535 ± 150.00040.8
[[File:Singh 81a.svgx130pxclass=skin-invert-image]]*R*-81a2β,3β835 ± 90480 ± 2137400 ± 14000.644.8
[[File:Singh 81b.svgx130pxclass=skin-invert-image]]*R*-81b2α,3β142 ± 1390 ± 3.42500 ± 2500.617.6
[[File:Singh 81c.svgx180pxclass=skin-invert-image]]*R*-81c2β,3α3.86 ± 0.25.62 ± 0.214.4 ± 1.31.43.7
[[File:Singh 81d.svgx130pxclass=skin-invert-image]]*S*-81d2β,3β1210 ± 33424 ± 1517300 ± 18000.314.3
[[File:Singh 81e.svgx130pxclass=skin-invert-image]]*S*-81e2α,3β27.6 ± 2.455.8 ± 5.731690 ± 1502.061.2
[[File:Singh 81f.svgx180pxclass=skin-invert-image]]*S*-81f2β,3α407 ± 3319 ± 1.81990 ± 1760.054.9

''N''-replaced (S,O,C)

The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.

CompoundX2 Groupconfig8DA5-HTNE
TropoxaneCl,ClCO2Me(racemic) β,βO
O-4210*p*-F3-methyl-5-isoxazoleβ,βS

8-oxa bridgehead replacements

StructureCompound #
(S. Singh)*Para*-
(*meta*-)DAT (IC50 *nM*)
displacement of [H3]WIN 354285-HTT (IC50 *nM*)
[H3]CitalopramSelectivity
5-HTT/DAT
[[File:Singh 90a.svg120pxclass=skin-invert-image]]*R/S*-90aH10001000-
[[File:Singh 90b.svg140pxclass=skin-invert-image]]*R/S*-90bF54625804.7
[[File:Singh 90c.svg140pxclass=skin-invert-image]]*R/S*-90cCl1010710.7
[[File:Singh 90d.svg140pxclass=skin-invert-image]]*R/S*-90dBr22301.4
[[File:Singh 90e.svg140pxclass=skin-invert-image]]*R/S*-90eI7121.7
[[File:Singh 90fg.svg140pxclass=skin-invert-image]]*R/S*-90f3,4-Cl23.356.521.9
[[File:Singh 90fg.svg140pxclass=skin-invert-image]]*R*-90g3,4-Cl23.274.671.4
[[File:Singh 90h.svg140pxclass=skin-invert-image]]*S*-90h3,4-Cl247581.2
[[File:Singh 91a.svg90pxclass=skin-invert-image]]*R/S*-91aH1990114405.7
[[File:Singh 91b.svg90pxclass=skin-invert-image]]*R/S*-91bF100010000-
[[File:Singh 91c.svg90pxclass=skin-invert-image]]*R/S*-91cCl28.581628.6
[[File:Singh 91d.svg90pxclass=skin-invert-image]]*R/S*-91dBr927630.7
[[File:Singh 91e.svg90pxclass=skin-invert-image]]*R/S*-91eI42721.7
[[File:Singh 91fg.svg100pxclass=skin-invert-image]]*R/S*-91f3,4-Cl23.0864.520.9
[[File:Singh 91fg.svg100pxclass=skin-invert-image]]*R*-91g3,4-Cl22.343113.2
[[File:Singh 91h.svg100pxclass=skin-invert-image]]*S*-91h3,4-Cl256286051.1

8-carba bridgehead replacements

StructureCompound #
(S. Singh)DAT (IC50 *nM*)
displacement of [H3]WIN 354285-HTT (IC50 *nM*)
[H3]CitalopramSelectivity
5-HTT/DAT
[[File:Phenyltropane analog 98a.svg140pxclass=skin-invert-image]]*R/S*-98a7.1 ± 1.75160 ± 580726
[[File:Phenyltropane analog 98b.svg140pxclass=skin-invert-image]]*R/S*-98b9.6 ± 1.833.4 ± 0.63.5
[[File:Phenyltropane analog 98c.svg100pxclass=skin-invert-image]]*R/S*-98c14.3 ± 1.1180 ± 6512.6

''N''-alkyl

File:RTI-242 structure.png File:Altropane.svg File:Ioflupane.png

CompoundX2 Groupconfig8DATSERTNET
FP-β-CPPITCl3′-phenylisoxazol-5′-ylβ,βNCH2CH2CH2F---
FE-β-CPPITCl(3′-phenylisoxazol-5′-yl)β,βNCH2CH2F---
Altropane (IACFT)FCO2Meβ,βNCH2CH=CHF---
last1=Wufirst1=Xiaoailast2=Caifirst2=Huaweilast3=Gefirst3=Ranlast4=Lifirst4=Linlast5=Jiafirst5=Zhiyuntitle=Recent Progress of Imaging Agents for Parkinson's Diseasejournal=Current Neuropharmacologyvolume=12issue=6year=2015pages=551–563issn=1570-159Xdoi=10.2174/1570159X13666141204221238pmc=4428027pmid=25977680}}ICO2Meβ,βNCH2CH2F---
RTI-310ICO2Meβ,βN-Prn1.17--
RTI-311ICO2Meβ,βNCH2CH=CH21.79--
RTI-312ICO2Meβ,βNBun0.76--
RTI-313ICO2Meβ,βNCH2CH2CH2F1.67--
Ioflupane (FP-CIT)123ICO2Meβ,βNCH2CH2CH2F---
PE2IMeCO2Meβ,βNCH2CH=CHI---
RTI-251ClCO2Meβ,βNCH2CO2Et1.9310.1114
RTI-252ClCO2Meβ,βNCH2CH2CO2Et2.5635.2125
RTI-242Clβ,β (bridged) -C(O)CH(CO2Me)CH2N7.67227510

Bi- and tri-cyclic aza compounds and their uses.

StructureShort Name
(S. Singh)Nitrogen side-chain
(N8)DAT
[3H]GBR 12935 *Ki* (nM)5-HTT
[3H]Paroxetine *Ki* (nM)NET
[3H]Nisoxetine *Ki* (nM)Selectivity
5-HTT/DATSelectivity
NET/DAT
CocaineH350 ± 80100003000028.6-
GBR 12909-0.06 ± 0.0252.8 ± 4.420000880-
WIN 35428
11bH14.7 ± 2.9181 ± 21635 ± 11012.343.2
RTI-55
11eH1.40 ± 0.200.46 ± 0.062.80 ± 0.400.32
[[File:Singh 82a.svg150pxclass=skin-invert-image]]82aCH2CH=CH222.6 ± 2.9**ɑ**----
[[File:Singh 82b.svg150pxclass=skin-invert-image]]82bCH2CH2CH343.0 ± 17.7**ɑ**----
[[File:Singh 82c.svg160pxclass=skin-invert-image]]82cCH2C6H558.9 ± 1.65**b**1073**c**-18.2-
[[File:Singh 82d.svg200pxclass=skin-invert-image]]82d(CH2)3C6H51.4 ± 0.2**b**133 ± 7**c**-95.0-
[[File:Singh 82e.svg210pxclass=skin-invert-image]]82e(CH2)5C6H53.4 ± 0.83**b**49.9 ± 10.2**c**-14.7-
[[File:Singh 83a.svg160pxclass=skin-invert-image]]83aCH2CH2CH2F1.20 ± 0.2948.7 ± 8.41000040.68333
[[File:Singh 83b.svg160pxclass=skin-invert-image]]83bCH2CH2F4.40 ± 0.3521.7 ± 8.3100004.9-
[[File:Singh 84a.svg160pxclass=skin-invert-image]]84aCH2CH2CH2F3.50 ± 0.390.110 ± 0.0263.0 ± 4.00.0318
[[File:Singh 84b.svg160pxclass=skin-invert-image]]84bCH2CH2F4.00 ± 0.730.140 ± 0.0293.0 ± 17.00.0323.2
[[File:Singh 84c.svg160pxclass=skin-invert-image]]84cCH2CHF215.1 ± 3.79.6 ± 1.550000.6-
[[File:Singh 84d.svg170pxclass=skin-invert-image]]84dCH2CH2CH2Cl3.10 ± 0.570.32 ± 0.0696.0 ± 29.00.131.0
[[File:Singh 84e.svg170pxclass=skin-invert-image]]84eCH2CH2CH2Br2.56 ± 0.570.35 ± 0.08164 ± 470.164.1
[[File:Singh 84f.svg170pxclass=skin-invert-image]]84fCH2CH2CH2I38.9 ± 6.38.84 ± 0.5350000.2128
[[File:Singh 84g.svg170pxclass=skin-invert-image]]84gCH2...methylcyclopropane4.30 ± 0.871.30 ± 0.25198 ± 9.60.346.0
[[File:Singh 84h.svg180pxclass=skin-invert-image]]84hCH2CH2CH2OH5.39 ± 0.212.50 ± 0.20217 ± 190.540.2
[[File:Singh 84i.svg200pxclass=skin-invert-image]]84iCH2CH2(OCH3)26.80 ± 1.101.69 ± 0.09110 ± 7.70.216.2
[[File:Singh 84j.svg180pxclass=skin-invert-image]]84jCH2CO2CH311.9 ± 1.40.81 ± 0.1029.1 ± 1.00.072.4
[[File:Singh 84k.svg185pxclass=skin-invert-image]]84kCH2CON(CH3)212.2 ± 3.86.40 ± 1.70522 ± 1450.542.8
[[File:Singh 84l.svg200pxclass=skin-invert-image]]84lCH2CH2CH2OMs36.3 ± 2.117.3 ± 1.250000.5138
[[File:Singh 84m.svg170pxclass=skin-invert-image]]84mCOCH(CH3)22100 ± 140102 ± 23100000.05-
[[File:Singh 84n.svg210pxclass=skin-invert-image]]84n(CH2)2Pht4.23 ± 0.480.84 ± 0.02441 ± 66.00.2104
[[File:Singh 84o.svg210pxclass=skin-invert-image]]84o(CH2)3Pht9.10 ± 1.100.59 ± 0.0774.0 ± 11.60.068.1
[[File:Singh 84p.svg230pxclass=skin-invert-image]]84p(CH2)4Pht2.38 ± 0.220.21 ± 0.02190 ± 18.00.0979.8
[[File:Singh 84q.svg230pxclass=skin-invert-image]]84q(CH2)5Pht2.40 ± 0.170.34 ± 0.0360.0 ± 3.100.125.0
[[File:Singh 84r.svg270pxclass=skin-invert-image]]84r(CH2)8Pht2.98 ± 0.300.20 ± 0.0275.0 ± 3.60.0725.2
[[File:Singh 84s.svg170pxclass=skin-invert-image]]84s**d**CH2CH=CH-CH315 ± 175 ± 5400 ± 805.026.7
[[File:Singh 84t.svg170pxclass=skin-invert-image]]84t**d**CH2C(Br)=CH230 ± 5200 ± 4010006.7-
[[File:Singh 84u.svg170pxclass=skin-invert-image]]84u**d**CH2CH=CH2I(E)30 ± 5960 ± 60295 ± 3332.09.8
[[File:Singh 84v.svg170pxclass=skin-invert-image]]84v**d**CH2C≡CH14 ± 1100 ± 3010007.1-
[[File:Singh 84w.svg170pxclass=skin-invert-image]]84w**d**CH2C6H542 ± 12100 ± 17600 ± 1002.414.3
[[File:Singh 84x.svg170pxclass=skin-invert-image]]84x**d**CH2C6H4-2-CH393 ± 19225 ± 4010002.4-
[[File:Singh 85a.svg160pxclass=skin-invert-image]]85a**d***para*-H113 ± 41100 ± 2010000.9-
[[File:Singh 85b.svg170pxclass=skin-invert-image]]85b**d***para*-Cl, *meta*-Cl29 ± 450 ± 6500 ± 1201.717.2
[[File:Singh 85c.svg170pxclass=skin-invert-image]]85c**d***para*-Me17 ± 7500 ± 30100029.4-
[[File:Singh 85d.svg180pxclass=skin-invert-image]]85d**d***para*-CH(CH3)2500 ± 120450 ± 8010000.9-
[[File:Singh 85e.svg190pxclass=skin-invert-image]]85e**d***para*-*n*-C3H7500 ± 100300 ± 12750 ± 1600.61.5
  • ɑIC50 for displacement of [3H]cocaine. IC50 for cocaine = 67.8 ± 8.7 (nM)
  • bIC50 values for displacement of [3H]WIN 35428
  • cIC50 values for displacement of [3H]citalopram
  • dThe standard Ki value for the displacement of [3H]GBR 12935, [3H]paroxetine, and [3H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments
Structure [[File:Di-subst thio sulfonyl nor-phenyltropanes.png150pxclass=skin-invert-image]]CompoundR1R2Inhibition of [3H]WIN 35,428
@ DAT
IC50 (nM)Inhibition of [3H]Paroxetine
@ 5-HTT
K*i* (nM)Inhibition of [3H]Nisoxetine
@ NET
K*i* (nM)NET/DAT
(uptake ratio)NET/5-HTT
(uptake ratio)
[See **7a—7h** table](3-4-disubstituted-phenyl-tropanes)
7aCH3CH39 ± 30.7 ± 0.2220 ± 1024314
7bC2H5CH3232 ± 344.5 ± 0.51170 ± 3005260
[[File:Phenyltropane 8a.svg160pxclass=skin-invert-image]]8aCH3H28 ± 60.19 ± 0.0121 ± 60.8110
[[File:Phenyltropane 8b.svg170pxclass=skin-invert-image]]8bC2H5H177 ± 621.26 ± 0.05118 ± 130.794
[[File:Phenyltropane 9a.svg210pxclass=skin-invert-image]]9aCH3FCH2CH2CH2112 ± 23 ± 1960 ± 1009320
[[File:Phenyltropane 9b.svg215pxclass=skin-invert-image]]9bC2H5FCH2CH2CH21,200 ± 20027 ± 22,000274
[[File:Phenyltropane 10a.svg200pxclass=skin-invert-image]]10aCH3CH2=CH2CH271 ± 255.5 ± 0.82,000 ± 50028364
[[File:Phenyltropane 10b.svg205pxclass=skin-invert-image]]10bC2H5CH2=CH2CH21,100 ± 10047 ± 32,000243
[[File:Phenyltropane 11a.svg200pxclass=skin-invert-image]]11aCH3CH3CH2CH274 ± 205.7 ± 0.61,200 ± 14016211
[[File:Phenyltropane 11b.svg205pxclass=skin-invert-image]]11bC2H5CH3CH2CH2900 ± 30049 ± 62,000241

Bridged ''N''-constrained phenyltropanes (fused/tethered)

See: Bridged cocaine derivatives & N8 Tricyclic (2β—crossed-over) N8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues

''p''-methyl aryl front & back ''N''-bridged phenyltropanes

Structures mentioned in US6150376 table of ''K<sub>i</sub>'' data.
Compound #
(*S. Singh's #*)2β=R[3H]Mazindol
binding[3H]DA
uptake[3H]5-HT
uptake[3H]NE
uptakeselectivity
[3H]5-HT/[3H]DA
cocaineCO2CH3375 ± 68423 ± 147155 ± 4083.3 ± 1.50.4
(–)-40
*(–)-128*54.3 ± 10.260.3 ± 0.41.76 ± 0.235.24 ± 0.070.03
(+)-40
*(+)-128*79 ± 19114 ± 281.48 ± 0.074.62 ± 0.310.01
(±)-40
*(±)-128*61.7 ± 8.560.3 ± 0.42.32 ± 0.232.69 ± 0.120.04
29β62014208030——
30β18649297.7——
31β47.021128.5——
29α4140201003920——
30α396088506961150—
45
*129*6.86 ± 0.4324.0 ± 1.31.77 ± 0.041.06 ± 0.030.07
42a
*131a**n*-Bu4.00 ± 0.072.23 ± 0.1214.0 ± 0.62.99 ± 0.176.3
41a
*130a**n*-Bu17.2 ± 1.1310.2 ± 1.478.9 ± 0.915.0 ± 0.47.8
42b
*131b*Et3.61 ± 0.4311.3 ± 1.125.7 ± 4.34.43 ± 0.012.3
50a
*133a**n*-Bu149 ± 6149 ± 2810 ± 8051.7 ± 125.4
49a
*132a**n*-Bu13.7 ± 0.814.2 ± 0.1618 ± 873.84 ± 0.3543.5
(–)-41050016500189070900—
(+)-41850027600463038300—
(–)-597409050119004650—
(+)-5677010500251004530—
RTI-4229/Coc-242N8/2β-C(O)CH(CO2Me)CH2N *para*-chloro—7.67 ± 0.31**ɑ**226.54 ± 27.37**b**510.1 ± 51.4**c**—
  • ɑValue for displacement of [3H]WIN 35,428 binding @ DAT
  • bValue for displacement of [3H]paroxetine binding to SERT
  • cValue for displacement of [3H]nisoxetine from NET Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4–5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130–133) preferred placement with DAT interaction.

3,4-Cl2 aryl front-bridged phenyltropanes

5998405}}
Frontbridged phenyltropane synthesis intermediate product compound #'''140'''
CodeCompoundDA (μM)NE (μM)5-HT (μM)
1(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11 -one O-methyl-oxime0.0120.00200.0033
2(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-one0.180.0350.0075
3(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime0.01600.00090.0032
4(1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol0.07500.00410.0028
5(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one0.120.00520.0026
6(1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol0.250.00740.0018
7(1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate0.210.00610.0075
8(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane0.0220.00140.0001
  1. 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
  2. 2° amine is reacted with Br(CH2)nCO2Et.
  3. Base used to abstract proton α- to CO2Et group and complete the tricyclic ring closure step (Dieckmann cyclization).

To make a different type of analog (see Kozikowski patent above)

  1. Remove N-Me
  2. Add ɣ-bromo-chloropropane
  3. Allow for cyclization with K2CO3 base and KI cat.

C2 + C3 (side-chain) fused (carboxylate & benzene conjoined)

Nitrogen-front-bridged indole phenyltropane.

(1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.02,10.04,9)pentadeca-4(9),5,7-trien-3-one

C3 to 1′ + 2′ (''ortho'') tropane locant dual arene bridged

Parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. Note that the carbomethoxyl group is (due to constraints in synthetic processes used in the creation of this compound) alpha configured; which is not the usual, most prevalent, conformation favored for the PT cocaine-receptor binding pocket of most such sub-type of chemicals. The above and below depictions show attested compounds synthesized, additionally with variations upon the Endo–exo isomerism of their structures.

Cycloalkane-ring alterations of the tropane ring system

Azanonane (outer ring extended)

3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives

To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs. Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.

Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.

StructureCompound #
(S. Singh)*Ki* (*nM*)
[[File:Kokain - Cocaine.svg220pxrightclass=skin-invert-image]]Cocaine32 ± 5
390 ± 220
[[File:WIN 35,065-2.svg150pxrightclass=skin-invert-image]]WIN 35065-233 ± 17
310 ± 220
[[File:Cocaine analog 146a.svg150pxleftclass=skin-invert-image]]146a4600 ± 510
[[File:Cocaine analog 146b.svg175pxleftclass=skin-invert-image]]146b5730 ± 570
[[File:Cocaine analog 146c.svg150pxleftclass=skin-invert-image]]146c3450 ± 310
[[File:Cocaine analog 146d.svg150pxleftclass=skin-invert-image]]146d3470 ± 350
[[File:Cocaine analog 147.svg100pxleftclass=skin-invert-image]]14713900 ± 2010

Azabornane (outer ring contracted)

3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives

Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.

Azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues (i.e. arrangements of differing locations for the nitrogens being either distal or proximal within the terms required to facilitate the framework of the compound to a correlative proportion, functional for the given moiety), were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane. Carroll, however, has listed benzoyloxy azabornanes in patents.

StructureCompound #
(S. Singh)*Ki* (*nM*)
[[File:Kokain - Cocaine.svg235pxrightclass=skin-invert-image]]Cocaine32 ± 5
390 ± 220
[[File:WIN 35,065-2.svg165pxrightclass=skin-invert-image]]WIN 35065-233 ± 17
310 ± 220
[[File:Cocaine analog 155a.svg150pxleftclass=skin-invert-image]]155a60,400 ± 4,800
[[File:Cocaine analog 155b.svg150pxleftclass=skin-invert-image]] [[File:Cocaine analog 155b alt.svg150pxrightclass=skin-invert-image]]155b96,500 ± 42
[[File:Cocaine analog 155c.svg150pxleftclass=skin-invert-image]]155c5,620 ± 390
[[File:Cocaine analog 155d.svg150pxleftclass=skin-invert-image]]155d18,900 ± 1,700

Piperidine [[Homologous series|homologues]] (inner two-carbon bridge excised)

Piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. Without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes.

''p''-chloro & related (piperidine homologues of phenyltropanes)

StructureCompound #
(S. Singh)X = *para*- / 4′-
SubstitutionR = 2-tropane positionDAT (IC50 *nM*)
[H3]WIN 35428 binding displacementDA (IC50 *nM*)
[H3]DA uptakeSelectivity
Uptake/Binding
[[File:Kokain - Cocaine.svg180pxrightclass=skin-invert-image]]
CocaineHCO2Me102 ± 9239 ± 12.3
[[File:Cocaine analog 166a.svg160pxleftclass=skin-invert-image]]
(±)-166aClβ-CO2CH353.7 ± 1.937.8 ± 7.90.7
(-)-166aClβ-CO2CH324.8 ± 1.685.2 ± 2.63.4
(+)-166aClβ-CO2CH31360 ± 1255090 ± 1723.7
[[File:Cocaine analog 167a.svg160pxleftclass=skin-invert-image]]
(-)-167aClβ-CO2OH75.3 ± 6.249.0 ± 3.00.6
(+)-167aClβ-CO2OH442 ± 32——
[[File:Cocaine analog 168a.svg160pxleftclass=skin-invert-image]]
(-)-168aClβ-CO2OAc44.7 ± 10.562.9 ± 2.71.4
(+)-168aClβ-CO2OAc928 ± 432023 ± 822.2
[[File:Cocaine analog 169a.svg160pxleftclass=skin-invert-image]]
[(-)-169a](1-methyl-3-propyl-4-p-chlorophenyl-piperidine)Clβ-*n*-Pr3.0 ± 0.58.3 ± 0.62.8
[[File:Cocaine analog 170a.svg150pxleftclass=skin-invert-image]]
(-)-170aHβ-CO2CH3769 ± 19——
[[File:Cocaine analog 166b.svg160pxleftclass=skin-invert-image]]
(±)-166bClα-CO2CH3197 ± 8——
(+)-166bClα-CO2CH357.3 ± 8.134.6 ± 3.20.6
(-)-166bClα-CO2CH3653 ± 38195 ± 80.3
[[File:Cocaine analog 167b.svg160pxleftclass=skin-invert-image]]
(+)-167bClα-CO2OH240 ± 18683 ± 472.8
[[File:Cocaine analog 168b.svg160pxleftclass=skin-invert-image]]
(+)-168bClα-CO2OAc461 ± 11——
[[File:Cocaine analog 169b.svg160pxleftclass=skin-invert-image]]
(+)-169bClα-*n*-Pr17.2 ± 0.523.2 ± 2.21.3

Heterocyclic N-Desmethyl

Naphthyl & related (piperidine homologues of phenyltropanes)

StructureCompound #DA uptake (nM)
IC50DA uptake (nM)
*Ki*NE uptake (nM)
IC50NE uptake (nM)
*Ki*5-HTT uptake (nM)
IC505-HTT uptake (nM)
*Ki*Uptake Ratio
DA/5-HT (*Ki*)Uptake Ratio
NE/5-HT (*Ki*)
[[File:Kokain - Cocaine.svg180pxrightclass=skin-invert-image]]Cocaine459 ± 159423 ± 147127 ± 4.1108 ± 3.5168 ± 0.4155 ± 0.42.70.69
[[File:Fluoxetine2DACS.svg180pxrightclass=skin-invert-image]]Fluoxetine45002500193 ± 4.1176 ± 3.58.1 ± 0.77.3 ± 0.762424
[[File:Cocaine analog Tamiz 20.svg170pxleftclass=skin-invert-image]]2075 ± 9.169 ± 8.1101 ± 3.388 ± 2.9440 ± 30391 ± 270.180.23
[[File:Cocaine analog Tamiz 6.svg170pxleftclass=skin-invert-image]]623 ± 1.021 ± 0.9-34 ± 0.88.2 ± 0.37.6 ± 0.22.84.5
[[File:Cocaine analog Tamiz 7.svg170pxleftclass=skin-invert-image]]71000947 ± 135-241 ± 1.78.2 ± 0.37.6 ± 0.222.65.7
[[File:Cocaine analog Tamiz 8.svg170pxleftclass=skin-invert-image]]894 ± 9.687 ± 8.9-27 ± 1.6209 ± 17192 ± 160.450.14
[[File:Cocaine analog Tamiz 9.svg170pxleftclass=skin-invert-image]]9293 ± 6.4271 ± 5.9-38 ± 4.013 ± 0.712 ± 0.7233.2
[[File:Cocaine analog Tamiz 19.svg180pxleftclass=skin-invert-image]]1997 ± 8.690 ± 8.034 ± 2.530 ± 2.33.9 ± 0.53.5 ± 0.5268.6
[[File:Cocaine analog Tamiz 10.svg140pxleftclass=skin-invert-image]]10326 ± 1.2304 ± 1.1337 ± 37281 ± 30113 ± 4.3101 ± 3.83.02.8
[[File:Cocaine analog Tamiz 14.svg180pxleftclass=skin-invert-image]]14144 ± 20131 ± 18204 ± 5.6175 ± 4.8155 ± 3.9138 ± 3.50.951.3
[[File:Cocaine analog Tamiz 15.svg180pxleftclass=skin-invert-image]]151800170013001100275 ± 39255 ± 3764
[[File:Cocaine analog Tamiz 16.svg180pxleftclass=skin-invert-image]]161000964 ± 10012001000334 ± 48309 ± 443.13.5
[[File:Cocaine analog Tamiz 17.svg170pxleftclass=skin-invert-image]]17213 ± 30187 ± 26399 ± 12364 ± 9.2189 ± 37175 ± 341.12.1
[[File:Cocaine analog Tamiz 18.svg180pxleftclass=skin-invert-image]]18184 ± 30173 ± 26239 ± 42203 ± 3667 ± 4.562 ± 4.12.83.3

distal-nitrogen 'dimethylamine' (piperidine-like cyclohexyl homologues of phenyltropanes)

Source:

cf. Fencamfamine

Radiolabeled

first2=Matilda }}</ref> Page 64. G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands.
CodeSERT Ki (nM)NET Ki (nM)DAT Ki (nM)RadiolabelIn vivo studyRefs.
10.2102.229.911CNon-human primate
20.231.732.611CNon-human primate
30.05243.47123IRat
40.08281318FNon-human primate
50.114502211CRat, monkey

File:N-3-iodoprop-(2E)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane.png|IPT (N-3-iodoprop-(2E)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane), can be radiolabeled with 123I or 125I and used as a ligand to map several MATs File:N-4-Fluorobut-2-yn-1-yl-2β-carbomethoxy-3β-phenyltropane.png|N-4-Fluorobut-2-yn-1-yl-2β-carbomethoxy-3β-phenyltropane (PR04.MZ) often radiolabeled. File:JHC 1-64.svg|JHC1-64. A fluorescent analog, similar in its long chain off of the nitrogen bridge similar to the transition metal phenyltropane types.

Transition metal complexes

These compounds include transition metals in their heteroatomic conformation, unlike non-radiolabel intended chelates where their element is chosen for intrinsic affectation to binding and function, these are tagged on by a "tail" (or similar) with a sufficient spacer to remain separated from known binding properties and instead are meant to add radioactivity enough to be easily tracked via observation methods that utilize radioactivity. As for anomalies of binding within the spectrum of the under-written kinds just mentioned: other factors not otherwise considered to account for its relatively lower potency, "compound 89c" is posited to protrude forward at the aryl place on its moiety toward the MAT ligand acceptor site in a manner detrimental to its efficacy. That is considered due to the steric bulk of the eight-position "tail" chelate substituted constituent, overreaching the means by which it was intended to be isolated from binding factors upon a tail, and ultimately nonetheless, interfering with its ability to bind. However, to broach this discrepancy, decreasing of the nitrogen tether at the eight position by a single methylene unit (89d) was shown to bring the potency of the analogous compound to the expected, substantially higher, potency: The N-methyl analog of 89c having an IC50 of 1.09 ± 0.02 @ DAT & 2.47 ± 0.14 nM @ SERT; making 89c upwards of thirty-three times weaker at those MAT uptake sites.

StructureCompound #
(S. Singh)X = *para*- / 4′-
SubstitutionConfigurationDAT (IC50 *nM*)
displacement of [H3]WIN 354285-HTT (IC50 *nM*)
[H3]CitalopramSelectivity
5-HTT/DAT+2β-chelated phenyltropanes
[[File:Phenyltropane 11b - WIN 35428.svg120pxrightclass=skin-invert-image]]WIN 35428F-11.0 ± 1.0160 ± 2014.5
[[File:Cocaine analog 73 - TRODAT-1.svg145pxleftclass=skin-invert-image]]73
TRODAT-1**ɑ**Cl-*R*=13.9, *S*=8.42**b**--
[[File:Cocaine analog 74 - TROTEC-1.svg170pxleftclass=skin-invert-image]]74
TROTEC-1F-high affinity site = 0.15 ± 0.04**c**
low affinity site = 20.3 ± 16.1**c**--
***N*-chelated phenyltropanes**
[[File:Cocaine analog 89a.svg200pxleftclass=skin-invert-image]]89aF2β5.99 ± 0.81124 ± 1720.7
[[File:Cocaine analog 89b.svg200pxleftclass=skin-invert-image]]89bF2α2960 ± 1575020 ± 18801.7
[[File:Cocaine analog 89c.svg200pxleftclass=skin-invert-image]]89c3,4-Cl22β37.2 ± 3.4264 ± 167.1
[[File:Cocaine analog 89d.svg200pxleftclass=skin-invert-image]]89dCl-0.31 ± 0.03**d**--
  • ɑIUPAC: [2-[[2-[[[3-(4-chlorophenyl)-7-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl]-(2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3—)-N2, N2′, S2, S2′]oxo-[1R-(exo, exo)]-[99mTc]technetium
  • bR- & S- isomer values are Ki (nM) for displacement of [125I]IPT with technetium-99m replaced by rhenium
  • cIC50 (nM) values for displacement of [3H]WIN 35428 with ligand tricarbonyltechnetium replaced with rhenium. (IC50 for WIN 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites)
  • dKi value for displacement of [125I]IPT radioligand.

Select annotations of above

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.

Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. , , , and .

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.

Sister substances

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

Most any variant with a tropane locant—3-β (or α) connecting linkage differing from, e.g. longer than, a single methylene unit (i.e. "phenyl"), including alkylphenyls (see the styrene analog, first image given in example below) is more correctly a "cocaine analogue" proper, and not a phenyltropane. Especially if this linkage imparts a sodium channel blocker functionality to the molecule.

References

Citations

[[Citation impact|Im-pact]] [[Citation index|indices]] (exact locations within sources cited) & [[Page footer|foot-notations]]

References

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