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.
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.
Takadoi
Masanori
M
Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1Nogi, Nogi-machi, Tochigi, 329-0114, Japan. masanori.takadoi@mb2.kyorin-pharm.co.jp
Yamaguchi
Kentaro
K
Terashima
Shiro
S
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
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