Structure-activity relationship studies of N-(9-benzyl)-9- azabicyclo[3.3.1]nonan-3-β-yl benzamide analogues for dopamine D₂ and D₃ receptors

A series of benzamide derivatives were prepared in order to determine the nature of the substituent effects in the benzamide aromatic ring on the affinity to dopamine D₂ and D₃ receptors. Both quantitative structure- activity relationship and molecular modeling (CoMFA) studies were conducted in order to identify the properties of the substituents important for receptor binding. Although traditional QSAR studies provided nearly identical equations for D₂ and D₃ receptor binding, CoMFA analysis indicated that there are subtle differences in both the steric and electronic properties of the D₂ and D₃ receptor in the region of the receptor recognizing the benzamide aromatic ring. These data should provide useful information in the design of second-generation analogs possessing a higher affinity for D₃ versus D₂ receptors.