Abstract
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.
MeSH terms
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Alkaloids / chemical synthesis
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Alkaloids / pharmacology
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Alzheimer Disease / drug therapy
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Animals
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Brain Stem / chemistry
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Cerebral Cortex / chemistry
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Furans / pharmacology
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Muscarinic Antagonists / chemical synthesis*
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Muscarinic Antagonists / pharmacology*
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Naphthalenes
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Parasympatholytics / chemical synthesis
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Parasympatholytics / pharmacology
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Piperidines / pharmacology
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Radioligand Assay
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Rats
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Receptor, Muscarinic M2
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Receptors, Muscarinic / chemistry*
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Receptors, Muscarinic / metabolism
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Stereoisomerism
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Structure-Activity Relationship
Substances
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3-demethylhimbacine
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Alkaloids
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Furans
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Muscarinic Antagonists
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Naphthalenes
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Parasympatholytics
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Piperidines
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Receptor, Muscarinic M2
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Receptors, Muscarinic
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himbacine