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• W1965622867 endingPage "2103" @default.
• W1965622867 startingPage "2094" @default.
• W1965622867 abstract "A set of amide- and amine-linked hybrid molecules comprising moieties of the orthosteric M1 muscarinic receptor agonist xanomeline and the cholinesterase inhibitor and allosteric receptor modulator tacrine were prepared with varying spacer length of 10−17 atoms. The hybrids inhibited acetylcholinesterase with similar or higher potency compared to tacrine. M1 receptor binding affinity was similar or higher relative to xanomeline and far higher relative to tacrine. Affinities hardly changed when the receptors’ orthosteric site was occupied by an inverse agonist ligand. When occupied by the orthosteric activator acetylcholine, affinity for the hybrids declined to unmeasureably low levels. Hybrids did not activate M1 receptors. In vivo studies assaying cognition impairment in rats induced by scopolamine revealed pronounced enhancement of scopolamine action. Taken together, instead of dualsteric (simultaneous allosteric/orthosteric) binding, the hybrids seem to prefer purely allosteric binding at the inactive M1 receptor." @default.
• W1965622867 created "2016-06-24" @default.
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• W1965622867 date "2010-02-16" @default.
• W1965622867 modified "2023-09-27" @default.
• W1965622867 title "Hybrid Molecules from Xanomeline and Tacrine: Enhanced Tacrine Actions on Cholinesterases and Muscarinic M₁ Receptors" @default.
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• W1965622867 doi "https://doi.org/10.1021/jm901616h" @default.
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