CONFORMATIONAL-ANALYSIS OF COCAINE, THE POTENT ANALOG 2-BETA-CARBOMETHOXY-3-BETA-(4-FLUOROPHENYL)TROPANE (CFT), AND OTHER DOPAMINE REUPTAKE BLOCKERS

Using the MM2-87 program and parameter set, conformational analyses have been performed on cocaine (1), the potent analog 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT, 2), and a group of dopamine reuptake blockers that contain two phenyl rings. The latter includes LU 19-005 (3), a 1-amino-4-phenyltetralin (4), a hexahydropyrrolo[2,1-a]isoquinoline (5), diclofensine (6), and a hexahydro[1,2-b]pyridine (7). Using different values for the dielectric constant, the global minimum of 1 and 2 is a conformer in which there is a favorable electrostatic interaction between the ammonium hydrogen and the carbonyl of the carbomethoxy group. The N-methyl groups in 1 and 2 are found to strongly prefer the equatorial position of the piperidine ring. These results were also related to four crystal structures of 1 and its close derivatives. Compounds 3-7 are found to have a common conformation that was used to define the pharmacophore for dopamine reuptake blockers including the required orientation of the ammonium hydrogen. The pharmacophore provides an explanation for why the tertiary amine analogs of 3 and 4 are less potent than the secondary amines because the added N-methyl group occupies the position required for the ammonium hydrogen. This explanation, however, does not work for 7, in which the tertiary amine is again less active than the secondary amine. However, this last series appears to have a number of anomalous features. Superposition of 2 with the pharmacophore suggests that its carbomethoxy may occupy the same region of the receptor as the second phenyl ring in compounds 3-7. (C) 1993 by John Wiley & Sons, Inc.