Norbenzomorphan Framework as a Novel Scaffold for Generating Sigma2 Receptor/PGRMC1 Subtype-Selective Ligands

A novel structural class with high affinity and subtype selectivity for the sigma2 receptor has been discovered. Preliminary structure-affinity relationship data are presented showing that 8-substituted 1,3,4,5-tetrahydro-1,5-methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma2 over the sigma1 receptor subtype. Indeed, piperazine analogue 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 sigma2 over the sigma1 receptor, thereby establishing it as one of the more subtype-selective sigma2 binding ligands reported to date. Emerging evidence has implicated the sigma2 receptor in multiple health disorders, so the drug-like characteristics of many of the selective sigma2 receptor ligands disclosed herein, coupled with their structural similarity to frameworks found in known drugs, suggest that norbenzomorphan analogues may be promising candidates for further development into drug leads.