title: Synthetic studies on himbacine, a potent antagonist of the muscarinic M2 subtype receptor. Part 2: synthesis and muscarinic M2 subtype antagonistic activity of the novel himbacine congeners modified at the C-3 position of lactone moiety.
abstract: With an aim to disclose the convergency and flexibility of our previously explored synthetic route to natural himbacine 1, and moreover, to clarify some novel aspects of the structure-activity relationships of 1, we prepared various structural types of novel himbacine congeners, 3-demethylhimbacine (3-norhimbacine) 2 and 4-epi-3-demethylhimbacine (4-epi-3-norhimbacine) 4-epi-2 and their enantiomers (ent-2 and ent-4-epi-2), 11-methylhimbacine 3, and 3-epihimbacine 4 in optically pure forms by employing our methodology. All of the synthesized congeners correspond to the compounds modified at the C-3 position of gamma-lactone moiety involved in 1. Among these congeners, 3-demethylhimbacine (3-norhimbacine) 2 was found to exhibit more potent muscarinic M(2) receptor binding affinity than natural 1.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1Nogi, Nogi-machi, Tochigi, 329-0114, Japan. masanori.takadoi@mb2.kyorin-pharm.co.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Takadoi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Shiro
authors.initials: S
authors.lastname: Terashima
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005663:Furans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D009281:Naphthalenes; D010880:Piperidines; D011813:Quinuclidinyl Benzilate; D051381:Rats; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D005663:Furans; D007202:Indicators and Reagents; D007783:Lactones; D018727:Muscarinic Antagonists; D009281:Naphthalenes; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate; C048172:himbacine