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Tropoxane

Chemical compound

Tropoxane (O-1072) is an aryloxytropane derivative drug developed by Organix Inc., which acts as a stimulant and potent dopamine and serotonin reuptake inhibitor. It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link (at the bridgehead position), demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.

Thia analog

The 8-thiabicyclo(3.2.1)octanes analogs such as O-4210 have been prepared. A representative set of analogs is listed below.

X	Com	DAT	SERT	Com	DAT	SERT	Com	DAT	SERT
H	1a	910	10uM	2a	140	8uM	3a	117	3uM
F	1b	220	30uM	2b	59	11uM	3b	38	494
Cl	1c	13	10uM	2c	11	1uM	3c	9.6	33
Br	1d	9.1	25uM	2d	6.0	342	3d	6.0	14
I	1e	6.7	8uM	2e	9.0	70	3e	14	10
Cl2	1f	4.5	3uM	2f	6.9	99	3f	5.7	8.0
BN	1g	8.0	1uM	2g	8.0	36	3g	16	13

It had been hypothesized that transporter binding of the tropanes might include ionic bonding of the central tropane nitrogen. But it turned out that at this site neither ionic nor hydrogen bonding is a prerequisite for potent monoamine reuptake inhibition. Oxa- and thia-analogs of RTI-111 are potent inhibitors, and even an N-replacement by methylene holds the potency within the same magnitude. However, N-quaternisation (N-dimethyl) considerably reduces DAT affinity.

In this SAR, the focus is on seeing the effect of changing 8-NMe to S, O, or CH2. Both enantiomers, as well as the racemates are presented in several cases for comparison.

Enant.	X	Com	DAT	SERT	Com	DAT	SERT	Com	DAT	SERT
Rac	S	1a	4.5	3,600	2a	6.9	99	3a	5.7	8.0
Rac	O	1a	10	6,000	2a	3.1	64.5	3a	3.3	6.5
1R	NMe	1a	1.2	867	2a	0.4	27	3a	1.1	2.5
Rac	CH2	1a	7.1	5,160	2a	13	166	3a	9.6	33

References

(March 1999). "Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry Letters.
"Bridge-substituted Tropanes and Uses".
(December 1996). "Nitrogen-based drugs are not essential for blockade of monoamine transporters". Synapse.
(August 1997). "2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters". Journal of Medicinal Chemistry.
(July 2000). "Molecular and regional targets of cocaine in primate brain: liberation from prosaic views". Addiction Biology.
(January 2007). "Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry.
(October 2003). "Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors". European Journal of Pharmacology.
(December 2001). "Non-amines, drugs without an amine nitrogen, potently block serotonin transport: novel antidepressant candidates?". Synapse.

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dopamine-reuptake-inhibitors chloroarenes methyl-esters oxygen-heterocycles heterocyclic-compounds-with-2-rings

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