SYNTHESIS, LIGAND-BINDING, AND QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF 3-BETA-(4-SUBSTITUTED PHENYL)-2-BETA-HETEROCYCLIC TROPANES - EVIDENCE FOR AN ELECTROSTATIC INTERACTION AT THE 2-BETA-POSITION

A set of 3 beta-(4'-substituted phenyl)-2 beta-heterocyclic tropanes w as designed, synthesized, and characterized. We discovered that these compounds can function as bioisosteric replacements for the correspond ing WIN 35,065-2 analogs which possess a 2 beta-carbomethoxy group. Se veral of the compounds showed high affinity and selectivity for the do pamine transporter (DAT) relative to the serotonin and norepinephrine transporters. From the structure-activity relationship study, the 3 be ta-(4'-chlorophenyl)-2 beta-(3'-phenylisoxazol-5-yl)tropane (5d) emerg ed as the most potent and selective compound. The binding data for 2 b eta-heterocyclic tropanes were found to show a high correlation with m olecular electrostatic potential (MEP) minima near one of the heteroat oms in the 2 beta-substituents, In contrast, low correlations were fou nd for other MEP minima near the 2 beta-substituent as well as for cal culated log P or substituent volume. These quantitative structure-acti vity relationship studies are consistent with an electrostatic contrib ution to the binding potency of these WIN 35,065-2 analogs at the DAT.