Lack of intrinsic activity and significant subtype selectivity of SR 95639A at muscarinic receptors.
We assessed the intrinsic activity of the purported selective muscarinic M1 receptor agonist SR 95639A (morpholinoethylamino-3-benzocyclohepta-(5,6-c)-pyridazine) in inducing several receptor-mediated signals. Our results indicate that SR 95639A lacks the ability to activate phosphoinositide hydrolysis in rat cerebral cortex or in Chinese hamster ovary cells transfected with the genes of the muscarinic m1 and m3 receptors. Similarly, this compound did not exhibit intrinsic activity in stimulating muscarinic receptors which inhibit cyclic AMP synthesis and did not suppress acetylcholine release in rat striatum. In addition, SR 95639A did not show a marked selectivity at the level of the ligand recognition site at the muscarinic M1, M2 and M3 receptors, since it bound to these receptor subtypes with equilibrium dissociation constants of 4, 6 and 11 microM, respectively.
Mohamed
A S
AS
Department of Pharmacology and Toxicology, University of Maryland School of Pharmacy, Baltimore 21201.
Forray
C
C
Aly
M H
MH
el-Fakahany
E E
EE
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D019832:N-Methylscopolamine; D011724:Pyridazines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000378:metabolism; D014162:Transfection
D007295:Inositol Phosphates; D009025:Morpholines; D011724:Pyridazines; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; C061233:morpholineoethylamino-3-benzocyclohepta(5,6-c)pyridazine; D005576:Colforsin; D002217:Carbachol; D000242:Cyclic AMP; D000109:Acetylcholine; D019832:N-Methylscopolamine