Selectivity of agonists for the active state of M1 to M4 muscarinic receptor subtypes. Export

@article{citeulike:4196875, 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 G alpha(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-chlorophenyl]carbamoyloxy)-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.}, author = {Figueroa, K. W. and Griffin, M. T. and Ehlert, F. J.}, citeulike-article-id = {4196875}, citeulike-linkout-0 = {http://dx.doi.org/10.1124/jpet.108.145219}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18824613}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18824613}, doi = {10.1124/jpet.108.145219}, issn = {1521-0103}, journal = {The Journal of pharmacology and experimental therapeutics}, keywords = {achr, muscarinic}, month = {January}, number = {1}, pages = {331--342}, posted-at = {2009-03-20 05:08:26}, priority = {2}, title = {Selectivity of agonists for the active state of M1 to M4 muscarinic receptor subtypes.}, url = {http://dx.doi.org/10.1124/jpet.108.145219}, volume = {328}, year = {2009} }

TY - JOUR ID - citeulike:4196875 L3 - citeulike-article-id:4196875 N2 - 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 G alpha(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-chlorophenyl]carbamoyloxy)-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. IS - 1 JF - The Journal of pharmacology and experimental therapeutics SN - 1521-0103 EP - 342 TI - Selectivity of agonists for the active state of M1 to M4 muscarinic receptor subtypes. VL - 328 SP - 331 KW - achr KW - muscarinic AU - Figueroa, KW AU - Griffin, MT AU - Ehlert, FJ PY - 2009/01// UR - http://dx.doi.org/10.1124/jpet.108.145219 ER -