title: Characterization of a new diphenylpyrazolidinone cholecystokinin antagonist in vitro isolated rat pancreatic acini.
abstract: The effects of a newly developed diphenylpyrazolidinone cholecystokinin (CCK) antagonist LY219,057 were examined in the isolated rat pancreatic acini and compared with those of devazepide (previously designated L364,718 or MK-329). LY219,057 caused a concentration-dependent inhibition of 100 pM CCK octapeptide (CCK-8)-stimulated amylase release, with a half-maximal inhibition (ID50) at 287.5 +/- 28.4 nM and was 200 times less potent than devazepide (ID50 = 1.4 +/- 0.2 nM). The antagonism was competitive in nature because LY219,057 caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase secretion without altering the maximal increase. LY219,057 significantly inhibited amylase release in response to CCK-8 and cerulein but had no effect on amylase release stimulated by other receptor secretagogs or agent bypassing receptors. LY219,057, whether added at the beginning or 20 min after the CCK-8 stimulation, inhibited amylase release. This compound caused a residual inhibition of the action of CCK-8. Acini preincubated with 1.0 microM LY219,057 for 30 min at 37 degrees C were threefold less sensitive to CCK-8 than the acini preincubated without LY219,057. These results indicate that LY219,057 acts as a potent, competitive, and specific CCK receptor antagonist of the action of CCK on the exocrine pancreas.
authors.affiliation: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Akiyama
authors.forename: I
authors.initials: I
authors.lastname: Tachibana
authors.forename: M
authors.initials: M
authors.lastname: Otsuki
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000037:antagonists & inhibitors
chemical_list: D001570:Benzodiazepinones; D011720:Pyrazoles; D011949:Receptors, Cholecystokinin; C085338:LY 219057; D000681:Amylases; D020109:Devazepide; D012844:Sincalide