Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands.

We report the design and synthesis of a series of enantiomerically pure hexahydropyrazinoquinolines as potent and selective ligands for the dopamine 3 subtype receptor using a newly developed synthetic method and using in vitro pharmacological evaluation. Our efforts yielded optically pure ligands with high affinities for the D3 receptor and outstanding selectivity over closely related D1-like and D2-like receptors. For example, compound 38a has a Ki value of 5.7 nM to the D3 receptor and selectivity greater than 10000- and 1600-fold over the D1-like and D2-like receptors, respectively, and thus is one of the most selective D3 ligands reported to date.