Further exploration of N-4 substituents on the piperazine ring of the hybrid template 5/ 7-{[2-(4-Aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol and its analog: development of an exceptionally potent agonist for D₂ & D₃ receptors

In this manuscript we report a structure-activity relationship (SAR) study of analogs of 5/ 7-{[2-(4-Aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol. Our study is focused on introduction of various bioisoteric and aromatic substitutions on the piperazine ring of the hybrid template to further probe into the accessory binding domains on dopamine D₂/D₃ receptors. Specifically, the goal behind this study is to delineate the nature of the binding pockets for such substitutions on the piperazine ring to determine their influence on binding affinity (Ki), as measured with tritiated spiperone and HEK-293 cells expressing either D₂ or D₃ receptors. Functional activity of selected compounds was assessed with the GTPγS binding assay. Our data indicates that various N-substitution with substituted and unsubstituted benzene sulfonyl group produced varied affinity and potency for D₂/D₃. Compound D-660 produced highest selectivity for the D₃ receptor in the binding assay. In general, presence of hydroxyl group improved overall activity for both D₂/D₃ receptors. One such compound D-668 produced exceptional potencies for both the receptors. Overall, our results suggest that binding to the sites removed from the orthosteric binding sites contribute significantly to enhance functional potencies of ligands.