Synthesis and muscarinic M(2) subtype antagonistic activity of enantiomeric pairs of 3-demethylhimbacine (3-norhimbacine) and its C(4)-epimer.
In the course of our studies of the structure-activity relationships of himbacine 1, a potent antagonist of the M(2) subtype of muscarinic receptor, the four title compounds, 2, ent-2, 3, and ent-3, were synthesized with a highly stereoselective intermolecular Diels-Alder reaction of tetrahydroisobenzofuran 4 with achiral furan-2(5H)-one 5 as a key step, followed by simultaneous optical resolution and epimer separation of the racemic intermediates. Among these compounds, 3-demethylhimbacine (3-norhimbacine) 2, bearing an absolute configuration corresponding to that of 1, was found to show more potent muscarinic M(2) subtype receptor binding activity than natural 1.
Takadoi
Masanori
M
Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1Nogi, Nogi-machi, Tochigi, Japan. masanori.takadoi@mb2.kyorin-pharm.co.jp
Yamaguchi
Kentaro
K
Terashima
Shiro
S
D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001933:Brain Stem / Q000737:chemistry; D002540:Cerebral Cortex / Q000737:chemistry; D005663:Furans / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D009281:Naphthalenes; D010276:Parasympatholytics / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C475585:3-demethylhimbacine; D000470:Alkaloids; D005663:Furans; D018727:Muscarinic Antagonists; D009281:Naphthalenes; D010276:Parasympatholytics; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C048172:himbacine