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

We previously identified hexahydrobenz[f]isoquinoline (4a) as a new class of dopamine 3 receptor (D3) ligand. Herein, we described the design, synthesis, and preliminary structure–activity relationships of new analogues of 4a as a novel class of D3 ligands. Among these new analogues, compound 4h is a potent D3 ligand (Ki = 6.1 nM) and has a selectivity of 133-fold between D3- and D2-like receptors, and of 163-fold between D3- and D1-like receptors, respectively. Thus, compound 4h represents a promising new lead compound for further design and optimization toward achieving highly potent and selective D3 ligands.