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Loxiglumide

A new proglumide analog with potent cholecystokinin antagonistic activity in the rat pancreas

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Abstract

D,l-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylamino)-5-oxopentanoic acid (CR 1505; loxiglumide) is a newly developed analog of proglumide. We examined the inhibitory effects of loxiglumide on pancreatic exocrine function in the isolated pancreatic acini and the isolated perfused pancreata of rats. Loxiglumide inhibited cholecystokinin octapeptide (CCK-8)-stimulated amylase release and, similarly, binding of[ 125 I]CCK-8 to isolated rat pancreatic acini. Loxiglumide was about 3000 times more potent than the reference substance proglumide, but was about 1000 times less potent than L-364,718, another new CCK antagonist having benzodiazepine ring, in inhibiting CCK-8-stimulated amylase release. The inhibitory effect of loxiglumide displayed competitive kinetics and was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. The inhibitory effect of loxiglumide was fully reversible in isolated acini. However, the pancreata perfused with 10 μM loxiglumide for 20 min did not respond to CCK-8 for more than 20 min even after the removal of loxiglumide infusion. In contrast, an immediate increase in pancreatic exocrine secretion was observed after proglumide removal. Loxiglumide appeared to be bound to the receptors on acinar cells in a slowly dissociating state. These results indicate that loxiglumide acts as a potent, competitive, and specific CCK antagonist on the exocrine pancreas and, because of its prolonged inhibitory action, may be useful as a therapeutic agent in pancreatic disease.

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References

  1. Steer ML, Meldolesi J: The cell biology of experimental pancreatitis. N Engl J Med 316:144–150, 1987

    PubMed  Google Scholar 

  2. Peikin SR, Costenbader CL, Gardner JD: Actions of derivatives of cyclic nucleotides on dispersed acini from guinea pig pancreas. Discovery of a competitive antagonist of the action of cholecystokinin. J Biol Chem 254:5321–5327, 1979

    PubMed  Google Scholar 

  3. Otsuki M, Okabayashi Y, Ohki A, Nakamura T, Tani S, Fujii S, Oka T, Sankaran H, Baba S: Effect of Bt2cGMP on action of cholescystokinin in isolated perfused rat pancreas. Am J Physiol 251:G293-G299, 1986

    PubMed  Google Scholar 

  4. Hahne WF, Jensen RT, Lem PH, Gardner JD: Proglumide and benzotript: Members of different class of cholecystokinin receptor antagonists. Proc Natl Acad Sci USA 78:6304–6308, 1981

    PubMed  Google Scholar 

  5. Lignon MF, Galas MC, Rodriguez M, Laur J, Aumelas A, Martinez J: A synthetic peptide derivative that is a cholecystokinin receptor antagonist. J Biol Chem 262:7226–7231, 1987

    PubMed  Google Scholar 

  6. Spanakel M, Martinez J, Briet C, Jensen RT, Gardner J: Cholecystokinin-27-32-amide. A member of a new class of cholecystokinin receptor antagonists. J Biol Chem 258:6746–6749, 1982

    Google Scholar 

  7. Change RSL, Lotti VJ, Monaghan RL, Birnbaum J, Stapley EO, Goetz MA, Albers-Schonberg G, Patchett AA, Liesch JM, Hensens OD, Springer JP: A potent non-peptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus. Science 230:177–179, 1985

    PubMed  Google Scholar 

  8. Chang RSL, Lotti VJ: Biochemical and pharmacological characterization of extremely potent and selective nonpeptide cholecystokinin antagonist. Proc Natl Acad Sci USA 83:4923–4926, 1986

    PubMed  Google Scholar 

  9. Chang RSL, Lotti VJ, Chen TB, Kunkel KA: Characterization of the binding of [3H]-(1)-L364718: A new potent non-peptide cholecystokinin antagonist radioligand selective for peripheral receptors. Mol Pharmacol 30:212–217, 1986

    PubMed  Google Scholar 

  10. Weiss J, Miederer SE (eds): Proglumide: Gastrin-Receptor Antagonist. Amsterdam, Excerpta Medica, 1980

    Google Scholar 

  11. Jensen RT, Murphy RB, Trampota M, Schneider LH, Jones SW, Howard JM, Gardner JD: Proglumide analogues: Potent cholecystokin in receptor antagonists. Am J Physiol 249:G214-G220, 1985

    PubMed  Google Scholar 

  12. Makovec F, Chiste R, Bani M, Pacini MA, Setnikar I, Rovati L: New glutaramic acid derivatives with potent competitive and specific cholecystokinin-antagonistic activity. Arzneim Forsch (Drug Res) 35:1048–1051, 1985

    Google Scholar 

  13. Jensen RT, Zhou ZH, Murphy RB, Jones SW, Setnikar I, Rovati LA, Gardner JD: Structural features of various proglumide-related cholecystokinin receptor antagonists. Am J Physiol 251:G839-G846, 1986

    PubMed  Google Scholar 

  14. Niederau C, Niederau M, Williams JA, Grendel JH: New proglumide-analogue CCK receptor antagonists: Very potent and selective for peripheral tissues. Am J Physiol 251:G856-G860, 1986

    Google Scholar 

  15. Makovec F, Bani M, Chiste R, Rovati LC, Rovati LA: Differentiation of central and peripheral cholecystokin in receptors by new glutaramic acid derivatives with cholecys-tokinin-antagonistic activity. Arzneim Forsch (Drug Res) 36:98–102, 1986

    Google Scholar 

  16. Hosotani H, Chowdhury P, McKay D, Rayford PL: Effect of L364718, a new CCK antagonist, on amylase secretion in isolated rat pancreatic acini. Pancreas 3:95–98, 1988

    PubMed  Google Scholar 

  17. Williams JA, Korc M, Dormer RL: Action of secretagogues on a new preparation of functionally intact, isolated pancreatic acini. Am J Physiol 235:E517-E524, 1978

    Google Scholar 

  18. Otsuki M, Williams JA: Effect of diabetes mellitus on the regulation of enzyme secretion by isolated rat pancreatic acini. J Clin Invest 70:148–156, 1982

    PubMed  Google Scholar 

  19. Ceska M, Birath K, Brown B: A new and rapid method for the clinical determination of α-amylase activities in human serum and urine. Clin Chim Acta 26:437–444, 1969

    PubMed  Google Scholar 

  20. Sankaran H, Goldfine ID, Deveney CW, Wong KY, Williams JA: Binding of cholecystokinin to high-affinity receptors on isolated rat pancreatic acini. J Biol Chem 255:1849–1853, 1980

    PubMed  Google Scholar 

  21. Sankaran H, Goldfine ID, Bailey AC, Licko V, Williams JA: Relationship of CCK receptor binding to regulation of biological functions in pancreatic acini. Am J Physiol 242:G250-G257, 1982

    PubMed  Google Scholar 

  22. Dehaye JP, Winand J, Poloczek P, Christophe J: Characterization of muscarinic cholinergic receptors on rat pancreatic acini byN-[3H]methylscopolamine binding. J Biol Chem 259:294–300, 1984

    PubMed  Google Scholar 

  23. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with Folin-phenol reagent. J Biol Chem 193:265–275, 1951

    PubMed  Google Scholar 

  24. Otsuki M, Sakamoto C, Yuu H, Maeda M, Morita S, Ohki A, Kobayashi N, Terashi K, Okano K, Baba S: Discrepancies between the doses of cholecystokinin or caerulein-stimulating exocrine and endocrine responses in perfused isolated rat pancreas. J Clin Invest 63:478–484, 1979

    PubMed  Google Scholar 

  25. Okabayashi Y, Otsuki M, Ohki A, Sakamoto C, Baba S: Effects of C-terminal fragments of cholecystokinin on exocrine and endocrine secretion from isolated perfused rat pancreas. Endocrinology 113:2210–2215, 1983

    PubMed  Google Scholar 

  26. Schild HO: Drug-receptor interactions.In Applied Pharmacology. HO Schild (ed). Edinburgh, Churchill Livingstone, 1980, pp 5–18

    Google Scholar 

  27. Jensen RT, Moody T, Pert C, River JE, Gardner JD: Interaction of bombesin and litrin with specific membrane receptors on pancreatic acinar cells. Proc Natl Acad Sci USA 75:6139–6143, 1978

    PubMed  Google Scholar 

  28. Christophe JP, Conlon TP, Gardner JD: Interaction of porcine vasoactive intestinal peptide with dispersed pancreatic acinar cells from the guinea pig. Binding of radioiodinated peptide. J Biol Chem 251:4629–4634, 1976

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Second Department of Internal Medicine, Kobe University School of Medicine, Kusunoki-cho, Chuo-ku, 650, Kobe, Japan

    Makoto Otsuki MD, Masatoshi Fujii MD, Takahiko Nakamura MD, Yoshinori Okabayashi MD, Satoshi Tani MD, Takashi Fujisawa MD, Makoto Koide MD & Shigeaki Baba MD

Authors
  1. Makoto Otsuki MD
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  2. Masatoshi Fujii MD
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  3. Takahiko Nakamura MD
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  4. Yoshinori Okabayashi MD
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  5. Satoshi Tani MD
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  6. Takashi Fujisawa MD
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  7. Makoto Koide MD
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  8. Shigeaki Baba MD
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Additional information

This work was supported in part by a grant from the Japanese Ministry of Health and Welfare (Intractable Diseases of the Pancreas).

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Otsuki, M., Fujii, M., Nakamura, T. et al. Loxiglumide. Digest Dis Sci 34, 857–864 (1989). https://doi.org/10.1007/BF01540270

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  • DOI: https://doi.org/10.1007/BF01540270

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