A number of substituted norbenzomorphans 1 have previously been shown to exhibit potent affinity and high selectivity for the sigma receptors (σRs), which include σ1R and σ2R, later identified by our lab as transmembrane protein 97 (σ2R/TMEM97). Several of compounds that were highly σ2R/TMEM97-selective were found to have novel therapeutic potential for a number of neurological conditions, including Alzheimer's disease, traumatic brain injury, Huntington’s disease, retinitis pigmentosa, alcohol use disorder, neuropathic pain, and alcohol-induced allodynia. Toward identifying compounds derived from alternate scaffolds, we engaged in the exercise of scaffold simplification by breaking rings and removing atoms. One such approach entailed cleaving a core bond of the norbenzomorphan ring system leading to 2-arylpiperidine analogs 2. Replacing a carbon atom in this ring with either an oxygen or nitrogen atom led to the corresponding analogs 3 and 4. These changes were guided by modeling studies that suggested that the orientations of the pharmacophoric elements, a hydrophobic group and a basic amino group, of the norbenzomorphans would be preserved in the simpler structures 2-4. Representative were prepared, and their binding profiles for σ1R receptor and the σ2R/TMEM97 were determined. Surprisingly, these compounds tended to have higher affinity for σ1R rather than σ2R/TMEM97 with selectivities up to about 14:1. In a separate series of experiments, we sought to identify other scaffolds related to the norbenzomorphan ring that might provide a suitable framework to orient the requisite pharmacophoric groups. Toward that end, we envisioned benzoxazocine ligands 5 that are derived by inserting an oxygen atom into a core bond of the norbenzomorphan ring might be interesting targets. This would result in only a small structural change but would afford more polar analogs that might have improved pharmacokinetic properties. We prepared a small set of aryl piperazine analogs and obtained their binding profiles for σ1R and σ2R/TMEM97. These compounds were generally somewhat selective for σ2R/TMEM97, but the most selective member of this group was only 5-fold selective.

Evaluating hetereoatomic monocycles and benzoxazocine based scaffolds for their sigma receptor binding capabilities

ACS Spring 2022

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