SELECTIVITY OF LG50643 FOR POSTJUNCTIONAL MUSCARINIC-RECEPTOR SUBTYPEIN THE GUINEA-PIG TRACHEA

The effects of (+/-)-LG50643, a new N-quaternary tropinic ester of phe nylcyclohexene carboxylic acid, endowed with a potent antimuscarinic a ctivity, have been investigated on muscarinic receptor-mediated respon ses of the guinea-pig trachea to electrical field stimulation. An isol ated preparation which allows the simultaneous measurement of tritiate d acetylcholine release (prejunctional effect) and smooth muscle contr action (postjunctional effect) was used. The guinea-pig epithelium-dep rived trachea was stimulated with 500 pulses (20 Hz, 1 ms, 9 V for 5 s , 30 s apart) in the presence of indomethacin (1 mum). Three successiv e pre- and postjunctional responses were observed. The potencies (-log EC50) of (+/-)-LG50643 for pre- and postjunctional muscarinic receptor s were determined and compared with those of selective muscarinic anta gonists. In addition, the affinity values of (+/-)-LG50643 for muscari nic-receptor subtypes were determined in radioligand binding experimen ts in cerebral cortex, heart and salivary glands of rat as target tiss ues for M1, M2 and M3 receptors, respectively. The results obtained in both functional and binding assays indicate (+/-)-LG50643 is a potent and selective antagonist for the M3-receptor subtype.