Lack of intrinsic activity and significant subtype selectivity of SR 95639A at muscarinic receptors

A. S. Mohamed; C. Forray; M. H.M. Aly; E. E. El-Fakahany

doi:10.1016/0922-4106(92)90126-G

Lack of intrinsic activity and significant subtype selectivity of SR 95639A at muscarinic receptors

A. S. Mohamed, C. Forray, M. H.M. Aly, E. E. El-Fakahany

Experimental and Clinical Pharmacology

Research output: Contribution to journal › Article › peer-review

Abstract

We assessed the intrinsic activity of the purported selective muscarinic M₁ receptor agonist SR 95639A (morpholinoethyl-amino-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 μM, respectively.

Original language	English (US)
Pages (from-to)	181-187
Number of pages	7
Journal	European Journal of Pharmacology: Molecular Pharmacology
Volume	227
Issue number	2
DOIs	https://doi.org/10.1016/0922-4106(92)90126-G
State	Published - Oct 1 1992

Bibliographical note

Funding Information:
Muscarinic acetylcholine receptors have been pharmacologically classified into three main subtypes termed neuronal M~, cardiac M 2 and glandular M3 (Doods et al., 1987; Hulme et al., 199(I). The existence of two additional subtypes of muscarinic receptors (m4 and m51 has been revealed by molecular cloning (Bonncr et a1.,1988). In senile dementia of the Alzheinler's type, there is impairment of cholinergic pathway.'; arising from basal forebrain which innervate the cerebral cortex and hippocampus (Whitehouse et al., 19851. However, there is preservation of the majority of post-synaptic muscarinic receptors in this disease (Quirion et at., 1989). Thus cholinergic replacement (._'orrespoudence to: Dr. Esaln E. EI-F~kahan~,. Ncur~;~;cicnce P,c search/Psychiatry, University of Minnesota Medical School. Box 392 Mayo, Minneapoli% MN 55455. USA. Tel. (6121 624-8432: Fax (6121 624-8935. This work was supported in par,, by Nllt grant NS-25743 and a grant from the U.S. Army Research Office. * Permanent address: Department of Pha,macology. Faculty of Medicine, Zagazig University. Benha, Egypt. Current address: Neur~geneties Corp., 215 Co!lege Rd.. Pavamus. NJ (17652, USA. ~ Current address: Division of Neuroscience Research in Psychiat,'3.'. University of Minnesota Medical Scht~)l. Box 392 May,,. Min-neap~lis, MN 55455. USA.

Keywords

Acetylcholine release
Muscarinic receptor agonists (selective)
Muscarinic receptor subtypes
Phosphoinositides
SR 95639A
cAMP

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title = "Lack of intrinsic activity and significant subtype selectivity of SR 95639A at muscarinic receptors",

abstract = "We assessed the intrinsic activity of the purported selective muscarinic M1 receptor agonist SR 95639A (morpholinoethyl-amino-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 μM, respectively.",

keywords = "Acetylcholine release, Muscarinic receptor agonists (selective), Muscarinic receptor subtypes, Phosphoinositides, SR 95639A, cAMP",

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note = "Funding Information: Muscarinic acetylcholine receptors have been pharmacologically classified into three main subtypes termed neuronal M~, cardiac M 2 and glandular M3 (Doods et al., 1987; Hulme et al., 199(I). The existence of two additional subtypes of muscarinic receptors (m4 and m51 has been revealed by molecular cloning (Bonncr et a1.,1988). In senile dementia of the Alzheinler's type, there is impairment of cholinergic pathway.'; arising from basal forebrain which innervate the cerebral cortex and hippocampus (Whitehouse et al., 19851. However, there is preservation of the majority of post-synaptic muscarinic receptors in this disease (Quirion et at., 1989). Thus cholinergic replacement (._'orrespoudence to: Dr. Esaln E. EI-F~kahan~,. Ncur~;~;cicnce P,c search/Psychiatry, University of Minnesota Medical School. Box 392 Mayo, Minneapoli% MN 55455. USA. Tel. (6121 624-8432: Fax (6121 624-8935. This work was supported in par,, by Nllt grant NS-25743 and a grant from the U.S. Army Research Office. * Permanent address: Department of Pha,macology. Faculty of Medicine, Zagazig University. Benha, Egypt. Current address: Neur~geneties Corp., 215 Co!lege Rd.. Pavamus. NJ (17652, USA. ~ Current address: Division of Neuroscience Research in Psychiat,'3.'. University of Minnesota Medical Scht~)l. Box 392 May,,. Min-neap~lis, MN 55455. USA.",

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AU - Forray, C.

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N2 - We assessed the intrinsic activity of the purported selective muscarinic M1 receptor agonist SR 95639A (morpholinoethyl-amino-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 μM, respectively.

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Lack of intrinsic activity and significant subtype selectivity of SR 95639A at muscarinic receptors

Abstract

Bibliographical note

Keywords

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