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

Pancreas. 1994 May;9(3):324-31. doi: 10.1097/00006676-199405000-00007.


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)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodiazepinones / pharmacology*
  • Devazepide
  • In Vitro Techniques
  • Indoles / pharmacology*
  • Male
  • Pancreas / drug effects*
  • Proglumide / analogs & derivatives
  • Proglumide / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Cholecystokinin / antagonists & inhibitors*
  • Sincalide / antagonists & inhibitors


  • Benzodiazepinones
  • Indoles
  • Receptors, Cholecystokinin
  • FR 120480
  • loxiglumide
  • Proglumide
  • Devazepide
  • Sincalide