The interaction of McN-A-343 with pirenzepine and other selective muscarine receptor antagonists at a prejunctional muscarine receptor.
The effect of several muscarine receptor antagonists on responses to carbachol (CCh) and McN-A-343 (McN) were compared in the perfused rabbit ear artery preparation stimulated via noradrenergic nerves at 3 Hz in the presence of cocaine (10 microM) and yohimbine (1 microM). The slope of the dose-response curve to McN was significantly less (P less than 0.05) than that for CCh although both agonists produced up to 100% inhibition of responses to nervous stimulation. All the antagonists investigated produced parallel shifts of the dose-response curve to the agonists and atropine, fenipramide or stercuronium gave a similar pA2 value with either agonist. Pirenzepine was a competitive antagonist when CCh was used, as judged by a slope of 0.96 +/- 0.10 for the Arunlakshana-Schild (A-S) plot (pKB 6.2). Displacement of 3H-(-)QNB binding by pirenzepine gave a pKI value of 6.0 which was not significantly different to the pKB value. When McN was used as the agonist, the dose-ratios obtained with pirenzepine (0.5 microM) were significantly different (P less than 0.01) to those with CCh as agonist and the slope of the A-S plot over the concentration range of 0.1 to 3 microM was significantly less than 1.0 (P less than 0.01), indicating that the inhibition was not a simple competitive interaction. It is suggested that the interaction of McN and pirenzepine may involve an allosteric mechanism.
Choo
L K
LK
Mitchelson
F
F
Vong
Y M
YM
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000378:metabolism / Q000494:pharmacology*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology*; D001667:Binding, Competitive; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D066298:In Vitro Techniques; D010197:Pancuronium / Q000494:pharmacology; D010890:Pirenzepine; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects*
D000470:Alkaloids; D001570:Benzodiazepinones; D000644:Quaternary Ammonium Compounds; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D001285:Atropine; D002217:Carbachol; D010197:Pancuronium; C003344:stercuronium