Pharmacological profile of a new serine derivative cholecystokinin receptor antagonist TP-680 on pancreatic, biliary and gastric function

Abstract

The in vivo pharmacological effects of the newly developed serine derivative [(R)-1-[3-(3-carboxypyridine-2-yl)thio-2-(indol-2-yl) carbonylamino]propionyl-4-diphenyl-methyl-piperazine] (TP-680), a cholecystokinin type-A (CCK-A) receptor antagonist, on pancreatic, biliary and gastric function were examined in rats and mice. The i.v. infusion of TP-680 in rats caused a parallel rightward shift of the entire dose-response curve for cholecystokinin octapeptide (CCK-8)-stimulated pancreatic exocrine secretion without altering the maximal response (ID50 = 480 nmol/kg). TP-680 also antagonized CCK-8-stimulated pancreatic secretion in mice (ID50 = 600 nmol/kg). Secretion of pancreatic juice and protein elicited by intraduodenal infusion of casein was also antagonized by TP-680. The CCK antagonism produced by i.v. TP-680 persisted for 16 h. Specificity for CCK was demonstrated by the inability of TP-680 (1000 nmol/kg) to antagonize either secretin- or bombesin-stimulated pancreatic secretion in rats. Moreover, specificity for CCK-A receptor was also demonstrated by the inability of TP-680 to antagonize pentagastrin-stimulated gastric acid secretion. Administered i.v., TP-680 was highly potent in antagonizing CCK-8-induced inhibition of gastric emptying (ID50 = 40 nmol/kg) but was less potent in antagonizing the contractile effects of CCK-8 on the gallbladder in mice (ID50 = 4000 nmol/kg). TP-680 also antagonized gallbladder contraction elicited by p.o. administered peptone. In the absence of exogenously administered CCK-8, TP-680 had no effect on any of the assay systems studied, which indicates a lack of CCK-like agonist properties. These results indicate that TP-680 is a potent, competitive and specific CCK-A receptor antagonist with long duration of action. The selectivity of TP-680 action depends on anatomical location of the CCK receptors (gastric emptying > pancreatic secretion > gallbladder contraction). This may provide a potentially valuable new tool for evaluating the role of CCK as a physiological mediator of GI function and its possible involvement in pathological states.