Synthesis and NMDA receptor affinity of dexoxadrol analogues with modifications in position 4 of the piperidine ring

Abstract

A series of dexoxadrol (3) analogues with various substituents at position 4 of the piperidine ring has been synthesized and pharmacologically evaluated. Key steps in the synthesis are a hetero-Diels–Alder reaction of the dioxolane-derived imine 10 with Danishefsky's diene 11 and replacement of the p-methoxybenzyl protective group by a Cbz group. All possible diastereomers were synthesized, respectively. It was shown that like-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4 substituent are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidine with a hydroxy moiety at position 4 (17d, WMS-2508, Ki = 44 nM) represents the most potent NMDA antagonist with high selectivity against σ1 and σ2 receptors, and the polyamine binding site of the NMDA receptor. The high sensitivity of the receptor ligand interaction became evident since methyl ethers with unlike-configuration of the ring junction (19a, 19b) prefer the σ1 receptor with high selectivity.