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, K_i = 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.