title: Conformationally constrained analogs of BAY 59-3074 as novel cannabinoid receptor ligands.
abstract: To obtain information on the pharmacophoric requirements of the CB1/CB2 partial agonist BAY 59-3074 we have synthesized a series of new conformationally constrained dibenzofuran (4a-d) and dibenzopyran analogs (5). All constrained analogs exhibited reduced binding affinity at both cannabinoid receptor subtypes, suggesting that planar conformations of these ligands are less favored by both receptors. We also found that 4c, 4d, and 5 exhibited 3- to 12-fold selectivity for hCB2 over rCB1 receptors and may serve as new chemotypes for the development of CB2-selective cannabinergics.
authors: Center for Drug Discovery, 116 Mugar Life Sciences Building, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, United States.
authors: Heidi
authors: H
authors: Teng
authors: Ganesh A
authors: GA
authors: Thakur
authors: Alexandros
authors: A
authors: Makriyannis
mesh_terms: D000476:Alkanesulfonates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D059350:Chronic Pain / Q000188:drug therapy / Q000503:physiopathology; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D012984:Software; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C498148:3-(2-cyano-3-(trifluoromethyl)phenoxy)phenyl-4,4,4-trifluoro-1-butanesulfonate; D000476:Alkanesulfonates; D000700:Analgesics; D001572:Benzofurans; D001578:Benzopyrans; D008024:Ligands; D009570:Nitriles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2