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

4-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]phenol (8) and 4-[3-(4-benzylpiperi din-1-yl)prop-1-ynyl phenol (9) are potent NR1A/2B receptor antagonists (IC 50 values 0.17 and 0.10 mu M, respectively). Administered intraperitoneally , they both potentiated the activity of L-DOPA in the unilaterally 6-hydrox ydopamine-lesioned (6-OHDA) rat, a model of Parkinson's disease. However, c ompound 9 was not active orally, likely due to rapid first-pass metabolism of the phenol moiety. The phenol was replaced by several bicyclic heterocyc lic systems containing an NH group to function as a H-bond donor in the hop e that these would be less likely to undergo rapid metabolism. In general, indoles, indazoles, benzotriazoles, indolones, and isatins gave analogues w ith weaker NR1A/2B activity than the parent phenols, while benzimidazolones and benzimidazolinones gave equipotent or more potent analogues. The prefe rence for a para arrangement between the H-bond donor and the linking acety lene moiety was confirmed, and a propyne link was preferred over a butyne l ink. Substitution on the benzyl group or a 4-hydroxyl group on the piperidi ne had little effect on NR1A/2B potency; however, 4-hydroxypiperidines demo nstrated slightly improved selectivity for NR1A/2B receptors versus alpha-1 adrenergic and dopamine D2 receptor affinity. From this study, 5-[3-(4-ben zylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzo-imidazol-2-one (46b) was id entified as a very potent, selective NR1A/2B receptor antagonist (IC50 valu e 0.0053 mu M). After oral administration at 10 and 30 mg/kg, 46b potentiat ed the effects of L-DOPA in the 6-OHDA-lesioned rat and seemed to have impr oved oral bioavailability but lower brain penetration compared to phenol 9.