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

A number of substituted norbenzomorphans have been previously identified as high affinity ligands for the two known sigma receptors s1R and s2R/TMEM97, and some norbenzomorphans that are selective for s2R/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 s1R and s2R/TMEM97 were determined. Consistent with our design strategy, N-acyl-2-arylpiperidines show high affinity for s2R/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 s1R and are thus s1Rselective. Computational docking studies show that representative 6-membered heterocycles bind and interact with s2R/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 s2R/TMEM97 ligands, but they also underscore the challenges associated with developing selective modulators of s2R/TMEM97. (c) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

Simplified analogs of norbenzomorphans show promise as high affinity ligands for s2R/TMEM97, but developing selective modulators remains challenging.