Structure-activity relationship studies of N-(9-benzyl)-9-azabicyclo[3.3.1]nonan-3-beta-yl benzamide analogues for dopamine D-2 and D-3 receptors

A series of benzamide derivatives were prepared in order to determine the n ature of the substituent effects in the benzamide aromatic ring on the affi nity to dopamine D-2 and D-3 receptors. Both quantitative structure-activit y relationship and molecular modeling (CoMFA) studies were conducted in ord er to identify the propel-ties of the substituents important for receptor b inding. Although traditional QSAR studies provided nearly identical equatio ns for D-2 and D-3 receptor binding, CoMFA analysis indicated that there ar e subtle differences in both the steric and electronic properties of the D- 2 and D-3 receptor in the region of the receptor recognizing the benzamide aromatic ring. These data should provide useful information in the design o f second-generation analogs possessing a higher affinity for D-3 versus D-2 receptors.