MUSCARINIC M(1) AND M(3) RECEPTOR ANTAGONIST EFFECTS OF A NEW PIRENZEPINE ANALOG IN ISOLATED GUINEA-PIG ILEAL LONGITUDINAL MUSCLE-MYENTERIC PLEXUS

The new pirenzepine analogue DF 545 has been tested for its muscarinic M(1) and M(3) receptor antagonist properties in guinea-pig longitudinal muscle-myenteric plexus preparations. McN-A-343-induced inhibition of twitch contractions was taken as a parameter for muscarinic M(1) receptor activation while electrical and acetylcholine-induced contractions were considered as a model for muscarinic M(3) receptor stimulation. An unexpected contractile effect evoked by McN-A-343 was also investigated. In contrast to pirenzepine, DF 545 only weakly counteracted the M(1)-mediated McN-A-343 inhibitory effect but blocked M(3)-related twitch- or acetylcholine-stimulated responses with a 2-fold higher affinity than pirenzepine. Therefore, in this preparation, our findings suggest that DF 545 does not share the selectivity profile exhibited by pirenzepine at ileal muscarinic receptors. Studies on the McN-A-343 contractile effect provide evidence that this agonist may interact with ileal muscarinic effector sites in a different way from other cholinergic agents.