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Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes

Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes Abstract We measured the intrinsic relative activity (RA i ) of muscarinic agonists to detect possible selectivity for receptor subtypes and signaling pathways. RA i is a relative measure of the microscopic affinity constant of an agonist for the active state of a GPCR expressed relative to that of a standard agonist. First, we estimated RA i values for a panel of agonists acting at the M 4 muscarinic receptor coupled to three distinct G-protein pathways: G i inhibition of cAMP accumulation, G s stimulation of cAMP accumulation, and Gα 15 stimulation of phosphoinositide hydrolysis. Our results show similar RA i values for each agonist, suggesting that the same active state of the M 4 receptor triggers the activation of the three G proteins. We also estimated RA i values for agonists across M 1 to M 4 muscarinic subtypes stably transfected in Chinese hamster ovary cells. Our results show selectivity of McN-A-343 4- I -3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammnonium chloride for the M 1 and M 4 subtypes and selectivity of pilocarpine for the M 1 and M 3 subtypes. The other agonists tested lacked marked selectivity among M 1 to M 4 receptors. Finally, we estimated RA i values from published literature on M 1 , M 2 , and M 3 muscarinic responses and obtained results consistent with our own studies. Our results show that the RA i estimate is a useful receptor-dependent measure of agonist activity. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Pharmacology and Experimental Therapeutics Am. Soc for Pharma & Experimental Therapeutics

Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes

Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes

The Journal of Pharmacology and Experimental Therapeutics , Volume 328 (1): 331 – Jan 1, 2009

Abstract

Abstract We measured the intrinsic relative activity (RA i ) of muscarinic agonists to detect possible selectivity for receptor subtypes and signaling pathways. RA i is a relative measure of the microscopic affinity constant of an agonist for the active state of a GPCR expressed relative to that of a standard agonist. First, we estimated RA i values for a panel of agonists acting at the M 4 muscarinic receptor coupled to three distinct G-protein pathways: G i inhibition of cAMP accumulation, G s stimulation of cAMP accumulation, and Gα 15 stimulation of phosphoinositide hydrolysis. Our results show similar RA i values for each agonist, suggesting that the same active state of the M 4 receptor triggers the activation of the three G proteins. We also estimated RA i values for agonists across M 1 to M 4 muscarinic subtypes stably transfected in Chinese hamster ovary cells. Our results show selectivity of McN-A-343 4- I -3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammnonium chloride for the M 1 and M 4 subtypes and selectivity of pilocarpine for the M 1 and M 3 subtypes. The other agonists tested lacked marked selectivity among M 1 to M 4 receptors. Finally, we estimated RA i values from published literature on M 1 , M 2 , and M 3 muscarinic responses and obtained results consistent with our own studies. Our results show that the RA i estimate is a useful receptor-dependent measure of agonist activity.

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Publisher
Am. Soc for Pharma & Experimental Therapeutics
Copyright
Copyright © Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565
eISSN
1521-0103
DOI
10.1124/jpet.108.145219
pmid
18824613
Publisher site
See Article on Publisher Site

Abstract

Abstract We measured the intrinsic relative activity (RA i ) of muscarinic agonists to detect possible selectivity for receptor subtypes and signaling pathways. RA i is a relative measure of the microscopic affinity constant of an agonist for the active state of a GPCR expressed relative to that of a standard agonist. First, we estimated RA i values for a panel of agonists acting at the M 4 muscarinic receptor coupled to three distinct G-protein pathways: G i inhibition of cAMP accumulation, G s stimulation of cAMP accumulation, and Gα 15 stimulation of phosphoinositide hydrolysis. Our results show similar RA i values for each agonist, suggesting that the same active state of the M 4 receptor triggers the activation of the three G proteins. We also estimated RA i values for agonists across M 1 to M 4 muscarinic subtypes stably transfected in Chinese hamster ovary cells. Our results show selectivity of McN-A-343 4- I -3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammnonium chloride for the M 1 and M 4 subtypes and selectivity of pilocarpine for the M 1 and M 3 subtypes. The other agonists tested lacked marked selectivity among M 1 to M 4 receptors. Finally, we estimated RA i values from published literature on M 1 , M 2 , and M 3 muscarinic responses and obtained results consistent with our own studies. Our results show that the RA i estimate is a useful receptor-dependent measure of agonist activity.

Journal

The Journal of Pharmacology and Experimental TherapeuticsAm. Soc for Pharma & Experimental Therapeutics

Published: Jan 1, 2009

References