RTI-336
Chemical compound
title: "RTI-336" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["4-chlorophenyl-compounds", "tropanes", "rti-compounds", "dopamine-reuptake-inhibitors", "stimulants", "isoxazoles", "4-tolyl-compounds"] description: "Chemical compound" topic_path: "general/4-chlorophenyl-compounds" source: "https://en.wikipedia.org/wiki/RTI-336" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0
::summary Chemical compound ::
| IUPAC_name = 5-[(1S,3S,4S,5R)-3-(4-Chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-4-yl]-3-(4-methylphenyl)-1,2-oxazole | image = RTI-336.svg | image_class = skin-invert-image | width= 175px
| tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration =
| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =
| CAS_number = 236754-02-2 | ATC_prefix = | ATC_suffix = | PubChem = 9800708 | ChEMBL_Ref = | ChEMBL = | UNII = 8QGL4KK64H | ChemSpiderID = 7976471
| C=24 | H=25 | Cl=1 | N=2 | O=1 | smiles = CC1=CC=C(C=C1)C2=NOC(=C2)[C@@H]3[C@H]4CCC@HC[C@@H]3C5=CC=C(C=C5) | StdInChI = 1S/C24H25ClN2O/c1-15-3-5-17(6-4-15)21-14-23(28-26-21)24-20(16-7-9-18(25)10-8-16)13-19-11-12-22(24)27(19)2/h3-10,14,19-20,22,24H,11-13H2,1-2H3/t19-,20+,22+,24-/m0/s1 | StdInChIKey = AUXUFNHAVGIVDC-IKJKNFHUSA-N | melting_point = | melting_high =
RTI-336, also known as RTI-4229-336 or LS-193,309 is a potent and selective dopamine reuptake inhibitor that was initially developed by the Research Triangle Institute, now known as RTI International.
Pharmacology
It is a phenyltropane derivative that binds to the dopamine transporter with approximately 20 times the affinity of cocaine. However, it produces relatively mild stimulant effects, with a slow onset and a long duration of action. (Although, other sources classify it as having among the faster onsets of action among phenyltropanes.)
Affinity of RIT-336 and analogs for the main monoamine transporters (DAT, NET, SERT):
::data[format=table]
| RTI | X | R | [3H]CFT | [3H]Nisoxetine | [3H]Paroxetine | N ÷ D | S ÷ D |
|---|---|---|---|---|---|---|---|
| Coc | — | — | 89.1 | 3298 (1986) | 1045 (45) | 37.01 | 11.79 |
| 177 | Cl | phenyl | 1.28 | 504 (304) | 2420 (220) | 393.8 | 1891 |
| 176 | Me | phenyl | 1.58 | 398 (239) | 5110 (465) | 251.9 | 3234 |
| 354 | Me | ethyl | 1.62 | 299 (180) | 6400 (582) | 184.6 | 3951 |
| 336 | Cl | p-tolyl | 4.09 | 1714 (1033) | 5741 (522) | 419.1 | 1404 |
| 386 | Me | p-anisyl | 3.93 | 756 (450) | 4027 (380) | 192.4 | 1025 |
| :: |
- [3H]CFT: [3H]CFT is a selective radioligand for the dopamine transporter (DAT)
- [3H]Nisoxetine: This is a radioligand for the norepinephrine transporter (NET)
- [3H]Paroxetine: This is a radioligand for the serotonin transporter (SERT)
- N ÷ D: ratio of norepinephrine transporter (NET) affinity to dopamine transporter (DAT) affinity
- S ÷ D: ratio of serotonin transporter (SERT) affinity to dopamine transporter (DAT) affinity
Animal studies
These characteristics make it a potential candidate for the treatment of cocaine addiction, as a possible substitute drug, analogous to the use of methadone for treating heroin dependence. RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration, and significantly reduces rates of cocaine use, especially when combined with SSRIs. Research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.
RTI-336 and RTI-177 exhibited lower reinforcing strength than cocaine in nonhuman primates, indicating reduced abuse liability and supporting their viability as pharmacotherapies for addiction.
Chronic RTI-336 administration in rhesus monkeys altered motor activity and sleep patterns but did not cause adverse hormonal changes, suggesting a relatively safe profile for long-term therapeutic use.
Clinical studies
A dosage of up to 20mg has been tolerated in healthy males.
References
References
- (January 2004). "Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3beta-(substituted phenyl)-2beta-(3'-substituted isoxazol-5-yl)tropanes". Journal of Medicinal Chemistry.
- (December 2006). "Effects of dopamine transporter selective 3-phenyltropane analogs on locomotor activity, drug discrimination, and cocaine self-administration after oral administration". European Journal of Pharmacology.
- (March 2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal.
- (March 2006). "Emerging pharmacological strategies in the fight against cocaine addiction". Expert Opinion on Emerging Drugs.
- (September 2008). "Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys". Pharmacology, Biochemistry, and Behavior.
- (February 2007). "Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys". The Journal of Pharmacology and Experimental Therapeutics.
- (September 2010). "Lower reinforcing strength of the phenyltropane cocaine analogs RTI-336 and RTI-177 compared to cocaine in nonhuman primates". Pharmacology, Biochemistry, and Behavior.
- (April 2012). "Influence of chronic dopamine transporter inhibition by RTI-336 on motor behavior, sleep, and hormone levels in rhesus monkeys". Experimental and Clinical Psychopharmacology.
- (10 July 2018). "A Double-Blind, Placebo-Controlled Trial Demonstrating the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of RTI-336". Frontiers in Pharmacology.
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