Subtype-selective N-methyl-D-aspartate receptor antagonists: Synthesis andbiological evaluation of 1-(arylalkynyl)-4-benzylpiperidines

A search of our compound library for compounds with structural similarity t o ifenprodil (5) and haloperidol (7) followed by in vitro screening reveale d that 4-benzyl-1-(4-phenyl-3-butynyl)-piperidine (8) was a moderately pote nt and selective antagonist of the NR1A/2B subtype of NMDA receptors. Subst itution on the benzyl group of 8 did not significantly affect NR1A/2B poten cy, while addition of hydrogen bond donors in the para position of the phen yl group enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-p osition of the piperidine group slightly reduced NR1A/2B potency while redu cing alpha-1 adrenergic and dopamine D2 receptor binding affinities substan tially, resulting in improved overall selectivity for NR1A/2B receptors. Fi nally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1A/2B pot ency order was butynyl > pentynyl >> propynyl. For the para methanesulfonam ide or hydroxyl groups, the order was butynyl approximate to propynyl > pen tynyl. 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 diseas e, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.