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

The present study examined the effects of a series of tricyclic muscar inic receptor antagonists on muscarinic receptors present in the guine a-pig ileum, both in vitro and in vivo. The selectivity profiles of th ese antagonists and that of atropine were determined by their affinity for cortical muscarinic M(1), cardiac M(2) and submandibular M(3) rec eptors and for m4 receptors expressed in CHO cells. The compounds pire nzepine, 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 th e most pronounced muscarinic M(1) selectivity. AF-DX 384 and AQ-RA 741 possessed an approximately 10-fold higher affinity for the cardiac mu scarinic M(2) receptor than AF-DX 116. However, both compounds also ex hibited high affinity for muscarinic m4 receptors. High affinity for m uscarinic M(3) and m4 receptors was observed for UH-AH 37, AQ-RA 391 a nd AQ-RA 681. The antagonists were then tested for their interaction w ith the muscarinic receptors which are responsible for the methacholin e-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 sh owing high affinity for muscarinic M(3) receptors (e.g. AQ-RA 618) wer e the most potent antagonists in the functional experiments. Compariso n of the binding displacement data with the functional results indicat es that the effects of methacholine on the longitudinal and circular m uscle of the guinea-pig ileum were predominantly mediated by muscarini c 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.