The interaction of McN-A-343 with pirenzepine and other selective muscarine receptor antagonists at a prejunctional muscarine receptor

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Abstract
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 μM) and yohimbine (1 μM). The slope of the dose-response curve to McN was significantly less (P2 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 of3H-(−)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 μM) were significantly different (PP<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.