Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists

[Image: see text] We report a class of potent and selective dopamine D(3) receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D(3) receptor (K(i) = 12.8 μM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has K(i) values of 2.7 and 2.8 nM at the rat and human dopamine D(3) receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D(2) receptors. Evaluation in a β-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D(3) receptor.