title: 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.
authors.affiliation: Third Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Tachibana
authors.forename: K
authors.initials: K
authors.lastname: Kanagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Otsuki
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000187:drug effects* / Q000502:physiology; D001839:Bombesin / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects; D008297:Male; D051379:Mice; D009525:Niacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects* / Q000502:physiology; D010418:Pentagastrin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012633:Secretin / Q000494:pharmacology; D012844:Sincalide / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects* / Q000502:physiology
chemical_list: D011949:Receptors, Cholecystokinin; C101187:TP 680; D012633:Secretin; D009525:Niacin; D010418:Pentagastrin; D003545:Cysteine; D012844:Sincalide; D001839:Bombesin