Design, synthesis, and evaluation of hexahydrobenz[f]isoquinolines as a novel class of dopamine 3 receptor ligands.

Abstract We previously identified hexahydrobenz[ f ]isoquinoline ( 4a ) as a new class of dopamine 3 receptor (D 3 ) ligand. Herein, we described the design, synthesis, and preliminary structure–activity relationships of new analogues of 4a as a novel class of D 3 ligands. Among these new analogues, compound 4h is a potent D 3 ligand ( K i  = 6.1 nM) and has a selectivity of 133-fold between D 3 - and D 2 -like receptors, and of 163-fold between D 3 - and D 1 -like receptors, respectively. Thus, compound 4h represents a promising new lead compound for further design and optimization toward achieving highly potent and selective D 3 ligands.