title: 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 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.
authors.affiliation: Department of Chemistry, University of Texas at Austin, 105 East 24th Street, Stop A5300, Austin, TX, 78712, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Sahn
authors.affiliation: Department of Chemistry, University of Texas at Austin, 105 East 24th Street, Stop A5300, Austin, TX, 78712, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hodges
authors.affiliation: Department of Chemistry, University of Texas at Austin, 105 East 24th Street, Stop A5300, Austin, TX, 78712, USA.
authors.forename: Jessica Z
authors.initials: JZ
authors.lastname: Chan
authors.affiliation: Department of Chemistry, University of Texas at Austin, 105 East 24th Street, Stop A5300, Austin, TX, 78712, USA. sfmartin@mail.utexas.edu.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Martin
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001575:Benzomorphans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011980:Receptors, Progesterone / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D000097605:Sigma-1 Receptor
chemical_list: D001552:Benzazepines; D001575:Benzomorphans; D008024:Ligands; D008565:Membrane Proteins; D010879:Piperazines; D011980:Receptors, Progesterone; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000618494:8-(4-(3-ethoxy-3-oxopropyl)piperazin-1-yl)-1,3,4,5-tetrahydro-1,5-methanobenzazepine-2-carboxylate; C486424:Pgrmc1 protein, rat; C106107:sigma-2 receptor
keywords: 1,5-methanobenzazepines; Sig2R/PGRMC1; norbenzomorphans; sigma 2 receptors