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. 1996 Apr;117(7):1558–1564. doi: 10.1111/j.1476-5381.1996.tb15321.x

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

T Akiyama 1, I Tachibana 1, Y Hirohata 1, H Shirohara 1, M Yamamoto 1, M Otsuki 1
PMCID: PMC1909435  PMID: 8730754

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.

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Selected References

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  1. Akiyama T., Otsuki M. Characterization of a new cholecystokinin receptor antagonist FK480 in in vitro isolated rat pancreatic acini. Pancreas. 1994 May;9(3):324–331. doi: 10.1097/00006676-199405000-00007. [DOI] [PubMed] [Google Scholar]
  2. Beglinger C., Hildebrand P., Adler G., Werth B., Luo H., Delco F., Gyr K. Postprandial control of gallbladder contraction and exocrine pancreatic secretion in man. Eur J Clin Invest. 1992 Dec;22(12):827–834. doi: 10.1111/j.1365-2362.1992.tb01453.x. [DOI] [PubMed] [Google Scholar]
  3. Beglinger C., Hildebrand P., Meier R., Bauerfeind P., Hasslocher H., Urscheler N., Delco F., Eberle A., Gyr K. A physiological role for cholecystokinin as a regulator of gastrin secretion. Gastroenterology. 1992 Aug;103(2):490–495. doi: 10.1016/0016-5085(92)90838-p. [DOI] [PubMed] [Google Scholar]
  4. Cantor P., Mortensen P. E., Myhre J., Gjorup I., Worning H., Stahl E., Survill T. T. The effect of the cholecystokinin receptor antagonist MK-329 on meal-stimulated pancreaticobiliary output in humans. Gastroenterology. 1992 May;102(5):1742–1751. doi: 10.1016/0016-5085(92)91738-p. [DOI] [PubMed] [Google Scholar]
  5. Ceska M., Birath K., Brown B. A new and rapid method for the clinical determination of alpha-amylase activities in human serum and urine. Optimal conditions. Clin Chim Acta. 1969 Dec;26(3):437–444. doi: 10.1016/0009-8981(69)90071-0. [DOI] [PubMed] [Google Scholar]
  6. Chang R. S., Lotti V. J. Biochemical and pharmacological characterization of an extremely potent and selective nonpeptide cholecystokinin antagonist. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4923–4926. doi: 10.1073/pnas.83.13.4923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fried M., Schwizer W., Beglinger C., Keller U., Jansen J. B., Lamers C. B. Physiological role of cholecystokinin on postprandial insulin secretion and gastric meal emptying in man. Studies with the cholecystokinin receptor antagonist loxiglumide. Diabetologia. 1991 Oct;34(10):721–726. doi: 10.1007/BF00401517. [DOI] [PubMed] [Google Scholar]
  8. GADDUM J. H., HAMEED K. A., HATHWAY D. E., STEPHENS F. F. Quantitative studies of antagonists for 5-hydroxytryptamine. Q J Exp Physiol Cogn Med Sci. 1955 Jan;40(1):49–74. doi: 10.1113/expphysiol.1955.sp001097. [DOI] [PubMed] [Google Scholar]
  9. Herrington M. K., Adrian T. E. On the role of cholecystokinin in pancreatic cancer. Int J Pancreatol. 1995 Apr;17(2):121–138. doi: 10.1007/BF02788530. [DOI] [PubMed] [Google Scholar]
  10. Hildebrand P., Beglinger C., Gyr K., Jansen J. B., Rovati L. C., Zuercher M., Lamers C. B., Setnikar I., Stalder G. A. Effects of a cholecystokinin receptor antagonist on intestinal phase of pancreatic and biliary responses in man. J Clin Invest. 1990 Mar;85(3):640–646. doi: 10.1172/JCI114486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hughes J., Boden P., Costall B., Domeney A., Kelly E., Horwell D. C., Hunter J. C., Pinnock R. D., Woodruff G. N. Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6728–6732. doi: 10.1073/pnas.87.17.6728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Liddle R. A., Gertz B. J., Kanayama S., Beccaria L., Coker L. D., Turnbull T. A., Morita E. T. Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK. J Clin Invest. 1989 Oct;84(4):1220–1225. doi: 10.1172/JCI114288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Makovec F., Chistè R., Bani M., Pacini M. A., Setnikar I., Rovati L. A. New glutaramic acid derivatives with potent competitive and specific cholecystokinin-antagonistic activity. Arzneimittelforschung. 1985;35(7):1048–1051. [PubMed] [Google Scholar]
  14. Meyer B. M., Werth B. A., Beglinger C., Hildebrand P., Jansen J. B., Zach D., Rovati L. C., Stalder G. A. Role of cholecystokinin in regulation of gastrointestinal motor functions. Lancet. 1989 Jul 1;2(8653):12–15. doi: 10.1016/s0140-6736(89)90255-9. [DOI] [PubMed] [Google Scholar]
  15. Mills J. G., Wood J. R. The pharmacology of histamine H2-receptor antagonists. Methods Find Exp Clin Pharmacol. 1989;11 (Suppl 1):87–95. [PubMed] [Google Scholar]
  16. Moran T. H., Robinson P. H., Goldrich M. S., McHugh P. R. Two brain cholecystokinin receptors: implications for behavioral actions. Brain Res. 1986 Jan 1;362(1):175–179. doi: 10.1016/0006-8993(86)91413-7. [DOI] [PubMed] [Google Scholar]
  17. Niederau C., Faber S., Karaus M. Cholecystokinin's role in regulation of colonic motility in health and in irritable bowel syndrome. Gastroenterology. 1992 Jun;102(6):1889–1898. doi: 10.1016/0016-5085(92)90310-u. [DOI] [PubMed] [Google Scholar]
  18. Niederau M., Niederau C., Strohmeyer G., Grendell J. H. Comparative effects of CCK receptor antagonists on rat pancreatic secretion in vivo. Am J Physiol. 1989 Jan;256(1 Pt 1):G150–G157. doi: 10.1152/ajpgi.1989.256.1.G150. [DOI] [PubMed] [Google Scholar]
  19. Otsuki M., Fujii M., Nakamura T., Okabayashi Y., Tani S., Fujisawa T., Koide M., Baba S. Loxiglumide. A new proglumide analog with potent cholecystokinin antagonistic activity in the rat pancreas. Dig Dis Sci. 1989 Jun;34(6):857–864. doi: 10.1007/BF01540270. [DOI] [PubMed] [Google Scholar]
  20. Otsuki M., Goldfine I. D., Williams J. A. Diabetes in the rat is associated with a reversible postreceptor defect in cholecystokinin action. Gastroenterology. 1984 Oct;87(4):882–887. [PubMed] [Google Scholar]
  21. Otsuki M., Williams J. A. Effect of diabetes mellitus on the regulation of enzyme secretion by isolated rat pancreatic acini. J Clin Invest. 1982 Jul;70(1):148–156. doi: 10.1172/JCI110588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rovati L. C. Perspectives of CCK antagonists in pancreatic research and clinical use. Part I. Int J Pancreatol. 1991 Apr;8(3):215–226. doi: 10.1007/BF02924540. [DOI] [PubMed] [Google Scholar]
  23. Saito A., Sankaran H., Goldfine I. D., Williams J. A. Cholecystokinin receptors in the brain: characterization and distribution. Science. 1980 Jun 6;208(4448):1155–1156. doi: 10.1126/science.6246582. [DOI] [PubMed] [Google Scholar]
  24. Schmidt W. E., Creutzfeldt W., Schleser A., Choudhury A. R., Nustede R., Höcker M., Nitsche R., Sostmann H., Rovati L. C., Fölsch U. R. Role of CCK in regulation of pancreaticobiliary functions and GI motility in humans: effects of loxiglumide. Am J Physiol. 1991 Feb;260(2 Pt 1):G197–G206. doi: 10.1152/ajpgi.1991.260.2.G197. [DOI] [PubMed] [Google Scholar]
  25. Setnikar I., Bani M., Cereda R., Chisté R., Makovec F., Pacini M. A., Revel L., Rovati L. C., Rovati L. A. Pharmacological characterisation of a new potent and specific nonpolypeptidic cholecystokinin antagonist. Arzneimittelforschung. 1987 Jun;37(6):703–707. [PubMed] [Google Scholar]
  26. Tani S., Itoh H., Koide M., Okabayashi Y., Otsuki M. Involvement of endogenous cholecystokinin in the development of acute pancreatitis induced by closed duodenal loop. Pancreas. 1993 Jan;8(1):109–115. doi: 10.1097/00006676-199301000-00019. [DOI] [PubMed] [Google Scholar]
  27. WROBLEWSKI F., LADUE J. S. Lactic dehydrogenase activity in blood. Proc Soc Exp Biol Med. 1955 Oct;90(1):210–213. doi: 10.3181/00379727-90-21985. [DOI] [PubMed] [Google Scholar]
  28. Woodruff G. N., Hughes J. Cholecystokinin antagonists. Annu Rev Pharmacol Toxicol. 1991;31:469–501. doi: 10.1146/annurev.pa.31.040191.002345. [DOI] [PubMed] [Google Scholar]

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