PHARMACOLOGICAL PROFILE OF SELECTIVE MUSCARINIC RECEPTOR ANTAGONISTS ON GUINEA-PIG ILEAL SMOOTH-MUSCLE

The present study examined the effects of a series of tricyclic muscarinic receptor antagonists on muscarinic receptors present in the guinea-pig ileum, both in vitro and in vivo. The selectivity profiles of these antagonists and that of atropine were determined by their affinity for cortical muscarinic M(1), cardiac M(2) and submandibular M(3) receptors and for m4 receptors expressed in CHO cells. The compounds pirenzepine, UH-AH 37, AQ-RA 391 and AQ-RA 618 possessed high affinity (pK(i) 7.94-8.22) for muscarinic M(1) receptors. Pirenzepine exhibited the most pronounced muscarinic M(1) selectivity. AF-DX 384 and AQ-RA 741 possessed an approximately 10-fold higher affinity for the cardiac muscarinic M(2) receptor than AF-DX 116. However, both compounds also exhibited high affinity for muscarinic m4 receptors. High affinity for muscarinic M(3) and m4 receptors was observed for UH-AH 37, AQ-RA 391 and AQ-RA 681. The antagonists were then tested for their interaction with the muscarinic receptors which are responsible for the methacholine-induced contraction of longitudinal muscle in vitro, circular muscle in vivo and muscarinic receptors which mediate the distension-evoked ascending reflex contraction of circular muscle in vitro. Compounds showing high affinity for muscarinic M(3) receptors (e.g. AQ-RA 618) were the most potent antagonists in the functional experiments. Comparison of the binding displacement data with the functional results indicates that the effects of methacholine on the longitudinal and circular muscle of the guinea-pig ileum were predominantly mediated by muscarinic M(3)-type receptors. In contrast, the correlation between muscarinic M(2) receptor affinity and antagonism of muscarinic receptors in the ileum was very weak.