Effect of loxiglumide (CR 1505) on CCK-induced contractions and 3H-acetylcholine release from guinea-pig gallbladder.

Abstract Release of [ 3 H]-acetylcholine ( 3 H-ACh) and muscle contractions in response to cholecystokinin (CCK) were measured and recorded simultaneously from isolated guinea-pig gallbladder. Cholecystokinin octapeptide (CCK8) (10 −10 –10 −7 M) enhanced the release of [ 3 H]ACh and the contractions of the muscle. TTX (10 −6 M) inhibited the CCK-induced release of 3 H-ACh by only 30%. In Ca 2+ -free medium CCK8 had no effect. Loxiglumide, (CR 1505), a newly synthesized nonpeptide CCK-A-receptor antagonist, D.L.- (3,4-dichlorbenzoilamino) -5 - / N - (3-methoxypropyl)-pentylamino-5-oxo-pentanoic acid, antagonized both the ACh-releasing effect of CCK and the contractions in a dose-dependent manner. The affinity (pA 2 ) of CR 1505 to CCK-receptors, determined by the shift of the concentration-response curves for CCK8 was 8.36. It was 5 logarithmic orders higher than the pA 2 of proglumide. The IC 50 value of CR 1505 calculated by the CCK-induced release of 3 H-ACh was 10 nM. The results suggest the existence not only of muscular CCK receptors but also neuronal receptors for CCK probably located on cholinergic nerves.