Abstract
Selective M1 cholinergic agonists may be useful in treating dementias due to cholinergic hypofunction. SR 95639 has recently been described as such a compound. We found the compound to have affinity for M1 sites (Ki = 2.1 microM) which was approximately 3-fold higher than its affinity for M2 sites. Functional partial agonism was suggested by an inconsistent increase in phosphoinositide (PI) turnover in rat hippocampal slices, combined with blockade of carbachol-stimulated PI turnover. In vivo M2-mediated effects were absent. Scopolamine-induced hyperactivity was attenuated by SR 95639 and scopolamine-impaired inhibitory avoidance and radial maze performance were improved. The compound appears to be a weakly selective M1 partial agonist with potential advantages over existing compounds.
MeSH terms
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Animals
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Avoidance Learning / drug effects
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Behavior, Animal / drug effects*
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Binding, Competitive / drug effects
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Body Temperature / drug effects
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Brain Chemistry / drug effects*
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Cerebellum / drug effects
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Cerebellum / metabolism
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Hippocampus / drug effects
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Hippocampus / metabolism
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In Vitro Techniques
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Learning / drug effects
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Male
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Morpholines / pharmacology*
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Motor Activity / drug effects
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Parasympathomimetics / pharmacology*
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Phosphatidylinositols / metabolism
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Pyridazines / pharmacology*
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Quinuclidinyl Benzilate / metabolism
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Rats
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Rats, Inbred Strains
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Receptors, Muscarinic / drug effects
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Receptors, Muscarinic / metabolism
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Scopolamine / pharmacology
Substances
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Morpholines
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Parasympathomimetics
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Phosphatidylinositols
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Pyridazines
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Receptors, Muscarinic
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morpholineoethylamino-3-benzocyclohepta(5,6-c)pyridazine
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Quinuclidinyl Benzilate
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Scopolamine