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 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. [Display omitted] •Simplified analogs of σ2R/TMEM97-selective B-norbenzomorphan designed and synthesized.•Binding studies show new ligands have high σ2R/TMEM97 affinity but are σ1R selective.•Computational docking studies show all ligands bind similarly to σ2R/TMEM97.•Binding and docking studies support rationale for design of simplified ligands.•Studies underscore difficulty of identifying σ2R/TMEM97-selective ligands.