Biomaterial Database

Characterization of a new cholecystokinin receptor antagonist FK480 in in vitro isolated rat pancreatic acini. 1994

T Akiyama, and M Otsuki

Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Biochemical and pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-N-[1-(2-fluorophenyl)-3,4, 6,7-tetrahydro-4-oxo-pyrrolo-[3,2,1-jk] [1,4]benzodiazepine-3-yl]-1H-indole-2-carboxamide (FK480) as a cholecystokinin (CCK) receptor antagonist were examined in the isolated rat pancreatic acini and compared with those of MK-329 and loxiglumide. FK480, MK-329, and loxiglumide inhibited CCK octapeptide (CCK-8)-stimulated amylase release and binding of [125I]CCK-8 in a concentration-dependent manner, with a half-maximal inhibition (ID50) at 1.30 +/- 0.12 nM, 1.33 +/- 0.21 nM, and 1.27 +/- 0.23 microM, respectively, for amylase release, and 0.40 +/- 0.06 nM, 0.68 +/- 0.08 nM, and 0.38 +/- 0.03 microM, respectively, for [125I]CCK-8 binding. The antagonism was competitive in nature because these three compounds caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase secretion, without altering the maximal increase. The antagonism produced by FK480 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. FK480 not only prevented but also reversed CCK-8-stimulated amylase release. This compound caused a residual inhibition of the action of CCK-8. When acini were preincubated with 100 nM FK480 for 30 min, the subsequent dose-response curve to CCK-8 was shifted 10-fold toward higher concentration. Similar results were obtained with MK-329 but not with loxiglumide. FK480 appeared to be bound to the receptors on acinar cells in a slowly dissociating state.(ABSTRACT TRUNCATED AT 250 WORDS)

UI	MeSH Term	Description	Entries
D007211	Indoles	Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008297	Male		Males
D010179	Pancreas	A nodular organ in the ABDOMEN that contains a mixture of ENDOCRINE GLANDS and EXOCRINE GLANDS. The small endocrine portion consists of the ISLETS OF LANGERHANS secreting a number of hormones into the blood stream. The large exocrine portion (EXOCRINE PANCREAS) is a compound acinar gland that secretes several digestive enzymes into the pancreatic ductal system that empties into the DUODENUM.
D011377	Proglumide	A drug that exerts an inhibitory effect on gastric secretion and reduces gastrointestinal motility. It is used clinically in the drug therapy of gastrointestinal ulcers.	Xylamide,Milid,Xilamide
D011949	Receptors, Cholecystokinin	Cell surface proteins that bind cholecystokinin (CCK) with high affinity and trigger intracellular changes influencing the behavior of cells. Cholecystokinin receptors are activated by GASTRIN as well as by CCK-4; CCK-8; and CCK-33. Activation of these receptors evokes secretion of AMYLASE by pancreatic acinar cells, acid and PEPSIN by stomach mucosal cells, and contraction of the PYLORUS and GALLBLADDER. The role of the widespread CCK receptors in the central nervous system is not well understood.	CCK Receptors,Caerulein Receptors,Cholecystokinin Octapeptide Receptors,Cholecystokinin Receptors,Pancreozymin Receptors,Receptors, CCK,Receptors, Caerulein,Receptors, Pancreozymin,Receptors, Sincalide,Sincalide Receptors,CCK Receptor,CCK-4 Receptors,CCK-8 Receptors,Cholecystokinin Receptor,Receptors, CCK-4,Receptors, CCK-8,Receptors, Cholecystokinin Octapeptide,CCK 4 Receptors,CCK 8 Receptors,Octapeptide Receptors, Cholecystokinin,Receptor, CCK,Receptor, Cholecystokinin,Receptors, CCK 4,Receptors, CCK 8
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001570	Benzodiazepinones
D012844	Sincalide	An octapeptide hormone present in the intestine and brain. When secreted from the gastric mucosa, it stimulates the release of bile from the gallbladder and digestive enzymes from the pancreas.	CCK-8,Cholecystokinin Octapeptide,CCK-OP,Cholecystokinin Pancreozymin C-Terminal Octapeptide,H-Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2,Kinevac,OP-CCK,SQ-19,844,SQ-19844,Syncalide,Cholecystokinin Pancreozymin C Terminal Octapeptide,SQ 19,844,SQ 19844,SQ19,844,SQ19844
D017208	Rats, Wistar	A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.	Wistar Rat,Rat, Wistar,Wistar Rats
D051381	Rats	The common name for the genus Rattus.	Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus