Biochemical and behavioral characterization of a novel cholinergic agonist, SR 95639.
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.
Boast
C A
CA
Wyeth-Ayerst Research, Princeton, NJ 08543-8000.
Leventer
S
S
Sabb
A
A
Abelson
M
M
Bender
R
R
Giacomo
D
D
Maurer
S
S
McArthur
S
S
Mehta
O
O
Morris
H
H
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007858:Learning / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010277:Parasympathomimetics / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology
D009025:Morpholines; D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011724:Pyridazines; D011976:Receptors, Muscarinic; C061233:morpholineoethylamino-3-benzocyclohepta(5,6-c)pyridazine; D011813:Quinuclidinyl Benzilate; D012601:Scopolamine