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

4-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]phenol ( 8 ) and 4-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]phenol ( 9 ) are potent NR1 a /2B receptor antagonists (IC 50 values 0.17 and 0.10 μM, respectively). Administered intraperitoneally, they both potentiated the activity of l -DOPA in the unilaterally 6-hydroxydopamine-lesioned (6-OHDA) rat, a model of Parkinson's disease. However, compound 9 was not active orally, likely due to rapid first-pass metabolism of the phenol moiety. The phenol was replaced by several bicyclic heterocyclic systems containing an NH group to function as a H-bond donor in the hope that these would be less likely to undergo rapid metabolism. In general, indoles, indazoles, benzotriazoles, indolones, and isatins gave analogues with weaker NR1 a /2B activity than the parent phenols, while benzimidazolones and benzimidazolinones gave equipotent or more potent analogues. The preference for a para arrangement between the H-bond donor and the linking acetylene moiety was confirmed, and a propyne link was preferred over a butyne link. Substitution on the benzyl group or a 4-hydroxyl group on the piperidine had little effect on NR1 a /2B potency; however, 4-hydroxypiperidines demonstrated slightly improved selectivity for NR1 a /2B receptors versus α-1 adrenergic and dopamine D2 receptor affinity. From this study, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-one ( 46b ) was identified as a very potent, selective NR1 a /2B receptor antagonist (IC 50 value 0.0053 μM). After oral administration at 10 and 30 mg/kg, 46b potentiated the effects of l -DOPA in the 6-OHDA-lesioned rat and seemed to have improved oral bioavailability but lower brain penetration compared to phenol 9 .