Norbenzomorphan Framework as a Novel Scaffold for Generating Sigma 2 Receptor/PGRMC1 Subtype‐Selective Ligands

Abstract

A novel structural class with high affinity and subtype selectivity for the sigma 2 receptor has been discovered. Preliminary structure affinity relationship data are presented showing that 8-substituted 2,3,4,5-tetrahydro-1,5-methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma 2 receptor over the sigma 1 receptor. Indeed, piperazine analog 8-(4-(3-ethoxy-3-oxopropyl)piperazin-1-yl)-1,3,4,5-tetrahydro-1,5-methanobenzazepine-2-carboxylate (SAS-1121) is 574-fold selective for the sigma 2 receptor over the sigma 1 receptor, thereby establishing it as one of the more subtype selective sigma 2 binding ligands reported to date. Emerging evidence has implicated the sigma 2 receptor in multiple health disorders, so the drug-like characteristics of many of the selective sigma 2 receptor ligands disclosed herein, coupled with their structural similarity to frameworks found in known drugs, suggest that norbenzomorphan analogs may be promising candidates for further development into drug leads.

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model

“…We surmise that norbenzomorphans identified in this and future applications of this powerful HCS assay may be promising leads as therapeutics for neurodegenerative conditions. 22 More generally, we expect this HCS microfluidic technology to be broadly applicable to test small molecules in C. elegans models that capture the subtle cellular phenotypes characteristic of the human disease. The ability to screen whole-animal models at unprecedented speeds and with high resolution will facilitate the identification and translation of promising preclinical candidates.…”

“…22,23 Briefly, the compounds were dissolved in 100% DMSO prior to the receptor binding assays, which were performed by the Psychoactive Drug Screening Program (PDSP) at Chapel Hill, North Carolina. The assay protocol book can be accessed free of charge at: http://pdspdb.unc.edu/pdspWeb/content/PDSP%20Protocols%20II%202013-03-28.pdf.…”

“…8,19,22 e Differs from previously published values due to averaging of additional of K i measurements. 8,22 …”

“…20,21 The discovery that neurodegenerative conditions might be mitigated via σ 2R/Tmem97 modulation inspired us to create larger sets of drug-like norbenzomorphans as novel ligands for σ 2R/Tmem97. 22,23 However, our ability to evaluate these compounds as neuroprotective agents in the SC_APP model was limited by the laborious nature of manually inspecting neuron health.…”

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease

“…We thus identified a subclass of substituted norbenzomorphans that bind to Sig2R with high affinity (Sahn and Martin ; Sahn et al . ). This is an important discovery because norbenzomorphans have compact molecular scaffolds and may be easily modified for structure‐activity relationship studies.…”