Tropoxane

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Tropoxane
Clinical data
ATC code
  • none
Identifiers
  • Methyl (1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylate
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC15H16Cl2O3
Molar mass315.19 g·mol−1
3D model (JSmol)
  • Clc1ccc(cc1Cl)[C@H]2C[C@H]3O[C@@H]([C@H]2C(=O)OC)CC3
  • InChI=1S/C15H16Cl2O3/c1-19-15(18)14-10(7-9-3-5-13(14)20-9)8-2-4-11(16)12(17)6-8/h2,4,6,9-10,13-14H,3,5,7H2,1H3/t9-,10+,13+,14-/m0/s1
  • Key:DHXANQGCRAVCSQ-PJQZNRQZSA-N
  (verify)

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 It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link (at the bridgehead position), demonstrating that the amine nitrogen is not required for DAT binding and reuptake inhibition.[3][4][5]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

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The 8-thiabicyclo(3.2.1)octanes analogs such as O-4210 have been prepared.[6] A representative set of analogs is listed below.

MAT IC50 (nM) 8-thiabicyclo[3.2.1]octanes
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.

MAT IC50 (nM) Cl2 bicyclo[3.2.1]octanes
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

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References

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  1. ^ Meltzer PC, Blundell P, Chen Z, Yong YF, Madras BK (March 1999). "Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry Letters. 9 (6): 857–62. doi:10.1016/s0960-894x(99)00098-0. PMID 10206550.
  2. ^ WO application 9740859, Madras BK, Meltzer PC, "Bridge-substituted Tropanes and Uses", published 6 November 1997, assigned to Harvard College 
  3. ^ Madras BK, Pristupa ZB, Niznik HB, Liang AY, Blundell P, Gonzalez MD, Meltzer PC (December 1996). "Nitrogen-based drugs are not essential for blockade of monoamine transporters". Synapse. 24 (4): 340–8. doi:10.1002/(SICI)1098-2396(199612)24:4<340::AID-SYN4>3.0.CO;2-D. PMID 10638825. S2CID 13410912.
  4. ^ Meltzer PC, Liang AY, Blundell P, Gonzalez MD, Chen Z, George C, Madras BK (August 1997). "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. doi:10.1021/jm9703045. PMID 9276012.
  5. ^ Madras BK, Miller GM, Meltzer PC, Brownell AL, Fischman AJ (July 2000). "Molecular and regional targets of cocaine in primate brain: liberation from prosaic views". Addiction Biology. 5 (3): 351–9. doi:10.1111/j.1369-1600.2000.tb00202.x. PMID 20575852. S2CID 26252206.
  6. ^ a b Pham-Huu DP, Deschamps JR, Liu S, Madras BK, Meltzer PC (January 2007). "Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters". Bioorganic & Medicinal Chemistry. 15 (2): 1067–82. doi:10.1016/j.bmc.2006.10.016. PMC 1829488. PMID 17070057.
  7. ^ Madras BK, Fahey MA, Miller GM, De La Garza R, Goulet M, Spealman RD, Meltzer PC, George SR, O'Dowd BF, Bonab AA, Livni E, Fischman AJ (October 2003). "Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors". European Journal of Pharmacology. 479 (1–3): 41–51. doi:10.1016/j.ejphar.2003.08.055. PMID 14612136.
  8. ^ Goulet M, Miller GM, Bendor J, Liu S, Meltzer PC, Madras BK (December 2001). "Non-amines, drugs without an amine nitrogen, potently block serotonin transport: novel antidepressant candidates?". Synapse. 42 (3). New York, N.Y.: 129–40. doi:10.1002/syn.1108. PMID 11746710. S2CID 22341553.
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