title: Characterization of the interaction of zamifenacin at muscarinic receptors in vitro.
abstract: The interaction of zamifenacin ((3R)-(+)-diphenylmethoxy-1-(3,4)-methylenedioxyphenethyl)pi peridine) at muscarinic receptor subtypes was studied using radioligand binding and functional techniques, in vitro. In radioligand binding studies, zamifenacin acted as a competitive antagonist, with the following pKi values; rat cerebral cortex (M1) 7.90 +/- 0.08, myocardium (M2) 7.93 +/- 0.13, submaxillary gland (M3) 8.52 +/- 0.04 and rabbit lung (M4) 7.78 +/- 0.04. In functional studies zamifenacin acted as a surmountable antagonist, exhibiting the following apparent affinity values; canine saphenous vein (putative M1) 7.93 +/- 0.09, guinea-pig left atria (M2) 6.60 +/- 0.04, guinea-pig ileum (M3) 9.31 +/- 0.06, guinea-pig oesophageal muscularis mucosae (M3) 8.84 +/- 0.04, guinea-pig trachea (M3) 8.16 +/- 0.04, and guinea-pig urinary bladder (M3) 7.57 +/- 0.15. Therefore, zamifenacin is selective for muscarinic M3 receptors in guinea-pig ileum, oesophageal muscularis mucosae, trachea and bladder over muscarinic M2 receptors in atria. The degree of muscarinic M3/M2 receptor selectivity depends upon the muscarinic M3 receptor preparation studied.
authors.affiliation: Institute of Pharmacology, Syntex Discovery Research, Palo Alto, CA 94303, USA.
authors.forename: N
authors.initials: N
authors.lastname: Watson
authors.forename: H
authors.initials: H
authors.lastname: Reddy
authors.forename: E
authors.initials: E
authors.lastname: Stefanich
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
mesh_terms: D000818:Animals; D004148:Dioxolanes / Q000494:pharmacology; D004149:Dioxoles / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism
chemical_list: D004148:Dioxolanes; D004149:Dioxoles; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010880:Piperidines; D011976:Receptors, Muscarinic; C010962:formal glycol; C097932:zamifenacin