Design, synthesis and structure-activity relationship studies of hexahydropyrazinoquinolines as a novel class of potent and selective dopamine receptor 3 (D3) ligands.

Abstract A hexahydropyrazinoquinoline (compound 5c ) was previously discovered as a novel D 3 ligand with a moderate binding affinity to the D 3 receptor ( K i  = 304 nM) but no selectivity over the D 1 -like and D 2 -like receptors. In this study, we wish to report the design, synthesis and structure–activity relationship studies of a series of novel hexahydropyrazinoquinolines. Our efforts resulted in new compounds with improved binding affinity and selectivity. Among them, compound 12d has a K i value of 2.6 nM for its binding affinity to the D 3 receptor and has >2000- and 99-fold selectivity over the D 1 -like and D 2 -like receptors, respectively, representing a potent and selective D 3 ligand.