Journal of Computer-Aided Molecular Design 2000-02-01

Conformational preferences of the potent dopamine reuptake blocker BTCP and its analogs and their incorporation into a pharmacophore model.

M Froimowitz, K M Wu, J Rodrigo, C George

Index: J. Comput. Aided Mol. Des. 14(2) , 135-46, (2000)

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Abstract

Molecular mechanics calculations using MM3-92 and ab initio quantum mechanical calculations using SPARTAN 5.0 were performed on the structurally similar PCP and BTCP, in which only the latter has a cocaine-like pharmacological profile as a dopamine reuptake blocker. Calculations were also performed on BTCP analogs with a methyl group in various positions of the cyclohexane ring. The results for the cis-2-methyl compound, which retains good pharmacological activity, allowed us to determine that an aryl-axial conformer is the biologically active form for at least some of the compounds in this series. However, an aryl-equatorial conformer presents the identical pharmacophore, as shown by superposition of the two conformers. X-ray crystallographic structures were also obtained for BTCP and related compounds with a 2-methyl group on the cyclohexane ring, with reasonable agreement between the computational and experimental results. Superposition studies were performed with two rigid analogs of cocaine which illustrate the optimal orientations of the ammonium hydrogen for monoamine transporters. There is excellent agreement between a 'back-bridged' cocaine analog that is optimal as a dopamine reuptake blocker and the previously proposed biologically active conformer of methylphenidate. However, BTCP is found to be a better fit to the 'front-bridged' cocaine analog that is optimal for a serotonin reuptake blocker.