Synthesis, Ligand Binding, and Quantitative Structure−Activity Relationship Study of 3β-(4‘-Substituted phenyl)-2β-heterocyclic Tropanes: Evidence for an Electrostatic Interaction at the 2β-Position

Abstract

A set of 3β-(4‘-substituted phenyl)-2β-heterocyclic tropanes was designed, synthesized, and characterized. We discovered that these compounds can function as bioisosteric replacements for the corresponding WIN 35,065-2 analogs which possess a 2β-carbomethoxy group. Several of the compounds showed high affinity and selectivity for the dopamine transporter (DAT) relative to the serotonin and norepinephrine transporters. From the structure−activity relationship study, the 3β-(4‘-chlorophenyl)-2β-(3‘-phenylisoxazol-5-yl)tropane (5d) emerged as the most potent and selective compound. The binding data for 2β-heterocyclic tropanes were found to show a high correlation with molecular electrostatic potential (MEP) minima near one of the heteroatoms in the 2β-substituents. In contrast, low correlations were found for other MEP minima near the 2β-substituent as well as for calculated log P or substituent volume. These quantitative structure−activity relationship studies are consistent with an electrostatic contribution to the binding potency of these WIN 35,065-2 analogs at the DAT.