Pharmacological profile of TP-680, a new cholecystokininA receptor antagonist

Br J Pharmacol. 1996 Apr;117(7):1558-64. doi: 10.1111/j.1476-5381.1996.tb15321.x.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amylases / metabolism
  • Animals
  • Benzodiazepinones / pharmacology
  • Binding, Competitive
  • Cerebral Cortex / metabolism
  • Cysteine / analogs & derivatives*
  • Cysteine / pharmacology
  • Devazepide
  • In Vitro Techniques
  • Intracellular Membranes / metabolism
  • Male
  • Niacin / analogs & derivatives*
  • Niacin / pharmacology
  • Pancreas / drug effects*
  • Pancreas / metabolism
  • Proglumide / analogs & derivatives
  • Proglumide / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Cholecystokinin A
  • Receptors, Cholecystokinin / antagonists & inhibitors*
  • Sincalide / antagonists & inhibitors


  • Benzodiazepinones
  • Receptor, Cholecystokinin A
  • Receptors, Cholecystokinin
  • TP 680
  • Niacin
  • loxiglumide
  • Amylases
  • Proglumide
  • Devazepide
  • Cysteine
  • Sincalide