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Norbenzomorphan Framework as a Novel Scaffold for Generating Sigma 2 Receptor/PGRMC1 Subtype‐Selective Ligands
Author(s) -
Sahn James J.,
Hodges Timothy R.,
Chan Jessica Z.,
Martin Stephen F.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500551
Subject(s) - sigma receptor , sigma , piperazine , sigma 1 receptor , selectivity , chemistry , stereochemistry , receptor , combinatorial chemistry , pharmacology , biology , biochemistry , agonist , physics , quantum mechanics , catalysis
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 1,3,4,5‐tetrahydro‐1,5‐methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma 2 over the sigma 1 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 sigma 2 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 analogues may be promising candidates for further development into drug leads.