Preparation of novel analogs of 2-arylpiperidines and evaluation of their sigma receptor binding affinities.

ID: ALA5154847

Journal: Eur J Med Chem

Title: Preparation of novel analogs of 2-arylpiperidines and evaluation of their sigma receptor binding affinities.

Authors: Walby GD, Martin SF.

Abstract: A number of substituted norbenzomorphans have been previously identified as high affinity ligands for the two known sigma receptors σ₁R and σ₂R/TMEM97, and some norbenzomorphans that are selective for σ₂R/TMEM97 exhibit promise in animal models of several neurological disorders. Toward further assessing the effects of simplifying the norbenzomorphan scaffold, sets of 6-membered heterocycles were designed and prepared, and their binding affinities for σ₁R and σ₂R/TMEM97 were determined. Consistent with our design strategy, N-acyl-2-arylpiperidines show high affinity for σ₂R/TMEM97, whereas those derived from morpholine and N-methylpiperazine have lower affinities. However, most of these 6-membered heterocycles unexpectedly exhibit even higher affinity for σ₁R and are thus σ₁R-selective. Computational docking studies show that representative 6-membered heterocycles bind and interact with σ₂R/TMEM97 in a manner similar to that of a docked structure of their norbenzomorphan parent. Collectively, these binding and computational studies support our design strategy for developing simplified analogs of norbenzomorphans as σ₂R/TMEM97 ligands, but they also underscore the challenges associated with developing selective modulators of σ₂R/TMEM97.

CiteXplore: 35395511

DOI: 10.1016/j.ejmech.2022.114310

Patent ID: ┄