Characterization of the interaction of zamifenacin at muscarinic receptors in vitro

Abstract The interaction of zamifenacin ((3 R )-(+)-diphenylmethoxy-1-(3,4)-methylenedioxyphenethyl)piperidine) 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 p K i values; rat cerebral cortex (M 1 ) 7.90 ± 0.08, myocardium (M 2 ) 7.93 ± 0.13, submaxillary gland (M 3 ) 8.52 ± 0.01 and rabbit lung (M 4 ) 7.78 ± 0.04. In functional studies zamifenacin acted as a surmountable antagonist, exhibiting the following apparent affinity values; canine saphenous vein (putative M 1 ) 7.93 ± 0.09, guinea-pig left atria (M 2 ) 6.60 ± 0.04, guinea-pig ileum (M 3 ) 9.31 ± 0.06, guinea-pig oesophageal muscularis mucosae (M 3 ) 8.84 ± 0.04, guinea-pig trachea (M 3 ) 8.16 ± 0.04, and guinea-pig urinary bladder (M 3 ) 7.57 ± 0.15. Therefore, zamifenacin is selective for muscarinic M 3 receptors in guinea-pig ileum, oesophageal muscularis mucosae, trachea and bladder over muscarinic M 2 receptors in atria. The degree of muscarinic M 3 M 2 receptor selectivity depends upon the muscarinic M 3 receptor preparation studied.