Chemistry:Tropoxane
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| Formula | C15H16Cl2O3 |
| Molar mass | 315.19 g·mol−1 |
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Tropoxane (O-1072)[1] is an aryloxytropane derivative drug developed by Organix Inc.,[2] 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 It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link (at the bridgehead position), demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.[3][4][5]
Thia analog
The 8-thiabicyclo(3.2.1)octanes analogs such as O-4210 have been prepared.[6] 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.[6][7][8] 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 |
See also
References
- ↑ "Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry Letters 9 (6): 857–62. March 1999. doi:10.1016/s0960-894x(99)00098-0. PMID 10206550.
- ↑ Madras BK, Meltzer PC, "Bridge-substituted Tropanes and Uses", WO patent application 9740859, published 6 November 1997, assigned to Harvard College
- ↑ "Nitrogen-based drugs are not essential for blockade of monoamine transporters". Synapse 24 (4): 340–8. December 1996. doi:10.1002/(SICI)1098-2396(199612)24:4<340::AID-SYN4>3.0.CO;2-D. PMID 10638825.
- ↑ "2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters". Journal of Medicinal Chemistry 40 (17): 2661–73. August 1997. doi:10.1021/jm9703045. PMID 9276012.
- ↑ "Molecular and regional targets of cocaine in primate brain: liberation from prosaic views". Addiction Biology 5 (3): 351–9. July 2000. doi:10.1111/j.1369-1600.2000.tb00202.x. PMID 20575852.
- ↑ 6.0 6.1 "Synthesis of 8-thiabicyclo[3.2.1octanes and their binding affinity for the dopamine and serotonin transporters"]. Bioorganic & Medicinal Chemistry 15 (2): 1067–82. January 2007. doi:10.1016/j.bmc.2006.10.016. PMID 17070057.
- ↑ "Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors". European Journal of Pharmacology 479 (1–3): 41–51. October 2003. doi:10.1016/j.ejphar.2003.08.055. PMID 14612136.
- ↑ "Non-amines, drugs without an amine nitrogen, potently block serotonin transport: novel antidepressant candidates?". Synapse (New York, N.Y.) 42 (3): 129–40. December 2001. doi:10.1002/syn.1108. PMID 11746710.
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