Effect of L364718, a new CCK antagonist, on amylase secretion in isolated rat pancreatic acini.

We examined the effect of L364718, a new cholecystokinin (CCK) receptor antagonist, on amylase release stimulated by CCK or different secretagogues in isolated rat pancreatic acini. L364718 caused a parallel rightward shift of the dose-response curve of CCK8. Schild plots showed a slope of 1.05 +/- 0.15 and a pA2 value of 10.01 +/- 0.31. L364718 inhibited maximally stimulated amylase release by CCK in a dose-dependent manner, with half maximal inhibition (ID50) at 1.7 nM and complete inhibition at 30 nM. Asperlicin, a prototype compound of L364718, also caused dose-dependent inhibition, but L364718 was approximately 400 times more potent than asperlicin (ID50 = 761 nM). L364718 significantly inhibited amylase release in response to CCK33 and CCK8 but had no effect on amylase release stimulated by other receptor secretagogues or agents by passing receptors. The results indicate that L364718 acts as an extremely potent, competitive, and specific antagonist of CCK's action on pancreatic acini.