title: Pharmacological profile of TP-680, a new cholecystokininA receptor antagonist.
abstract: 1. The pharmacological characteristics of a newly developed serine derivative (R)-1-[3-(3-carboxypyridine-2-yl) thio-2-(indol-2-yl)carbonylamino]propionyl-4-diphenylmethyl- piperazine (TP-680), a cholecystokinin type A (CCKA) receptor antagonist, were studied and compared with those of MK-329 and loxiglumide. 2. TP-680 showed approximately 2 and 22 times greater selectivity for peripheral CCKA receptors relative to brain CCK (CCKB) receptors than MK-329 and loxiglumide, respectively, when IC50 values for inhibition of [125I]-CCK-8 binding in isolated acini and cerebral cortex were compared. 3. TP-680 was approximately 17 times less potent than MK-329, but was 106 times more potent than loxiglumide in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. The antagonism produced by TP-680 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. 4. TP-680 caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase release as did MK-329 and loxiglumide. However, in contrast to MK-329 and loxiglumide, TP-680 suppressed the maximal responses of CCK-8-induced amylase release in a concentration-dependent fashion, indicating that TP-680 is an unsurmountable antagonist. 5. Repeated washing of acini after a 30 min treatment with TP-680 restored the responsiveness but not the sensitivity, causing a residual inhibition on the action of CCK-8. 6. The addition of loxiglumide prior to or together with application of TP-680 protected CCK receptors from unsurmountable and irreversible antagonism by TP-680. 7. Our results indicate that TP-680 is a potent and the most selective CCKA receptor antagonist for the pancreas reported to date.
authors.affiliation: Third Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Akiyama
authors.forename: I
authors.initials: I
authors.lastname: Tachibana
authors.forename: Y
authors.initials: Y
authors.lastname: Hirohata
authors.forename: H
authors.initials: H
authors.lastname: Shirohara
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Otsuki
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020109:Devazepide; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D009525:Niacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000037:antagonists & inhibitors
chemical_list: D001570:Benzodiazepinones; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; C101187:TP 680; D009525:Niacin; C053737:loxiglumide; D000681:Amylases; D011377:Proglumide; D020109:Devazepide; D003545:Cysteine; D012844:Sincalide