Subtype-Selective N-Methyl-d-aspartate Receptor Antagonists:  Synthesis and Biological Evaluation of 1-(Arylalkynyl)-4-benzylpiperidines

A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)piperidine (8) was a moderately potent and selective antagonist of the NR1a/2B subtype of NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1a/2B potency, while addition of hydrogen bond donors in the para position of the phenyl group enhanced NR1a/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group slightly reduced NR1a/2B potency while reducing α-1 adrenergic and dopamine D2 receptor binding affinities substantially, resulting in improved overall selectivity for NR1a/2B receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1a/2B potency order was butynyl > pentynyl ≫ propynyl. For the para methanesulfonamide or hydroxyl groups, the order was butynyl ≈ propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the most potent NR1a/2B antagonists from this study. They both potentiated the effects of l-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.