Synthesis of N-substituted 4-(4-hydroxyphenyl)piperidines, 4-(4-hydroxybenzyl)piperidines, and (+/-)-3-(4-hydroxyphenyl)pyrrolidines: selective antagonists at the 1A/2B NMDA receptor subtype.

Antagonists at the 1a/2B subtype of the NMDA receptor (NR1a/2B) are typically small molecules that consist of a 4-benzyl- or a 4-phenylpiperidine with an ω-phenylalkyl substituent on the heterocyclic nitrogen. Many of these antagonists, for example ifenprodil (1), incorporate a 4-hydroxy substituent on the ω-phenyl group. In this study, the position of this 4-hydroxy substituent was transferred from the ω-phenyl group to the benzyl or phenyl group located on the 4-position of the piperidine ring. Analogues incorporating pyrrolidine in lieu of piperidine were also prepared. Electrical recordings using cloned receptors expressed in Xenopus oocytes show that high-potency antagonists at the NR1a/2B subtype are obtained employing N-(ω-phenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine, 4-(4-hydroxybenzyl)piperidine, and (±)-3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC50 = 0.022 μM), 33 (IC50 = 0.059 μM), and 40 (IC50 = 0.017 μM), respectively. These high-potency antagonists are >1000 times more ...