title: In vitro muscarinic activity of spiromuscarones and related analogs.
abstract: The cholinergic hypothesis of Alzheimer's disease suggests that cholinergic agonists may have therapeutic potential for treating the attendant memory deficits of the disease. As part of a program aimed at preparing metabolically stable, nonquaternary analogs of muscarone, 1-oxa-2,8-dimethyl-8-azaspiro[4.5]decan-3-one, 2a, and related analogs have been synthesized and their in vitro muscarinic activity evaluated. The synthetic strategy in the formation of the 1-spiro[4.5]decan-3-one ring system of 2a involved cyclization of the diol 4 in the presence of Nafion-Hg. The spiromuscarone 2a was found to displace [3H]Oxo-M binding with a Ki value of 7 nM. Affinities of the oxime and hydrazone analogs of 2a were lower than 2a. The compounds in these series were partial muscarinic agonists as demonstrated by stimulation of phosphatidyl inositol hydrolysis assay, with 2a showing the highest intrinsic intrinsic activity (60% as compared with carbachol). The results from this study indicate that an exo double bond at the C-3 position is essential for the receptor binding.
authors.affiliation: Department of Chemistry and Biology, Fisons Pharmaceuticals, Rochester, New York 14623, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Wu
authors.forename: R C
authors.initials: RC
authors.lastname: Griffith
authors.forename: J T
authors.initials: JT
authors.lastname: Loch
authors.forename: A
authors.initials: A
authors.lastname: Kover
authors.forename: R J
authors.initials: RJ
authors.lastname: Murray
authors.forename: G B
authors.initials: GB
authors.lastname: Mullen
authors.forename: J C
authors.initials: JC
authors.lastname: Blosser
authors.forename: A C
authors.initials: AC
authors.lastname: Machulskis
authors.forename: S A
authors.initials: SA
authors.lastname: McCreedy
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009116:Muscarine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018721:Muscarinic Agonists; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018721:Muscarinic Agonists; C002394:muscarone; D009116:Muscarine