Pharmacological characterization of rebamipide: Its cholecystokinin CCK ₁ receptor binding profile and effects on Ca ²⁺ mobilization and amylase release in rat pancreatic acinar cells

We previously reported that rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)- quinolinon-4-yl]-propionic acid) generated oscillations of intracellular Ca ²⁺ concentration ([Ca ²⁺] _i) probably through the activation of cholecystokinin type 1 (CCK ₁) receptors in rat pancreatic acinar cells. Therefore, in the present study, we aimed to establish the pharmacological characteristics of rebamipide in rat pancreatic acinar cells. CCK-8S and rebamipide inhibited [ ¹²⁵I]BH-CCK-8S binding to rat pancreatic acinar cell membranes with IC ₅₀ values of 3.13 nM and 37.7 μM, respectively. CCK-8S usually evoked [Ca ²⁺] _i oscillations at concentrations lower than 50 pM, and it induced biphasic [Ca ²⁺] _i increases at higher concentrations. In contrast to CCK-8S, rebamipide only induced [Ca ²⁺] _i oscillations at all the concentrations we used in this study. In addition, rebamipide was shown to inhibit high concentrations of CCK-8S-induced biphasic increases in [Ca ²⁺] _i, suggesting that rebamipide might be a partial agonist at cholecystokinin CCK ₁ receptors. Although rebamipide induced [Ca ²⁺] _i oscillations by activating the cholecystokinin CCK ₁ receptors, rebamipide did not cause amylase release and only inhibited CCK-stimulated amylase release reversibly and dose-dependently. However, rebamipide did not inhibit carbachol-, vasoactive intestinal polypeptide (VIP)-, and forskolin-induced amylase releases. These data indicate that rebamipide functions as a partial agonist for Ca ²⁺-mobilizing action, and it is also an antagonist for the amylase-releasing action of CCK.