AJP - Gastrointestinal and Liver Physiology, Vol 254, Issue 2 176-G182, Copyright © 1988 by American Physiological Society

ARTICLES

Structure-activity relationship studies on cholecystokinin: analogues with partial agonist activity

M. C. Galas, M. F. Lignon, M. Rodriguez, C. Mendre, P. Fulcrand, J. Laur and J. Martinez
Centre de Pharmacologie-Endocrinologie, Montpellier, France.

In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of 125I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini.

This article has been cited by other articles:

				C. H. Kubisch and C. D. Logsdon Secretagogues differentially activate endoplasmic reticulum stress responses in pancreatic acinar cells Am J Physiol Gastrointest Liver Physiol, June 1, 2007; 292(6): G1804 - G1812. [Abstract] [Full Text] [PDF]

				M. Dufresne, C. Seva, and D. Fourmy Cholecystokinin and gastrin receptors. Physiol Rev, July 1, 2006; 86(3): 805 - 847. [Abstract] [Full Text] [PDF]

				T. O. Lankisch, Y. Tsunoda, Y. Lu, and C. Owyang Characterization of CCKA receptor affinity states and Ca2+ signal transduction in vagal nodose ganglia Am J Physiol Gastrointest Liver Physiol, June 1, 2002; 282(6): G1002 - G1008. [Abstract] [Full Text] [PDF]

				C. Escrieut, V. Gigoux, E. Archer, S. Verrier, B. Maigret, R. Behrendt, L. Moroder, E. Bignon, S. Silvente-Poirot, L. Pradayrol, et al. The Biologically Crucial C Terminus of Cholecystokinin and the Non-peptide Agonist SR-146,131 Share a Common Binding Site in the Human CCK1 Receptor. EVIDENCE FOR A CRUCIAL ROLE OF MET-121 IN THE ACTIVATION PROCESS J. Biol. Chem., February 22, 2002; 277(9): 7546 - 7555. [Abstract] [Full Text] [PDF]

				R. Poosti, L. di Malta, D. Gagne, N. Bernad, J.-C. Galleyrand, C. Escrieut, S. Silvente-Poirot, D. Fourmy, and J. Martinez The Third Intracellular Loop of the Rat and Mouse Cholecystokinin-A Receptors Is Responsible for Different Patterns of Gene Activation Mol. Pharmacol., April 13, 2001; 58(6): 1381 - 1388. [Abstract] [Full Text]

				F. Noble, S. A. Wank, J. N. Crawley, J. Bradwejn, K. B. Seroogy, M. Hamon, and B. P. Roques International Union of Pharmacology. XXI. Structure, Distribution, and Functions of Cholecystokinin Receptors Pharmacol. Rev., December 1, 1999; 51(4): 745 - 781. [Abstract] [Full Text] [PDF]

				J. A. Tapia, H. A. Ferris, R. T. Jensen, and L. J. Garcia Cholecystokinin Activates PYK2/CAKbeta by a Phospholipase C-dependent Mechanism and Its Association with the Mitogen-activated Protein Kinase Signaling Pathway in Pancreatic Acinar Cells J. Biol. Chem., October 29, 1999; 274(44): 31261 - 31271. [Abstract] [Full Text] [PDF]

				V. Gigoux, C. Escrieut, J.-A. Fehrentz, S. Poirot, B. Maigret, L. Moroder, D. Gully, J. Martinez, N. Vaysse, and D. Fourmy Arginine 336 and Asparagine 333 of the Human Cholecystokinin-A Receptor Binding Site Interact with the Penultimate Aspartic Acid and the C-terminal Amide of Cholecystokinin J. Biol. Chem., July 16, 1999; 274(29): 20457 - 20464. [Abstract] [Full Text] [PDF]

				E. Bignon, A. Bachy, R. Boigegrain, R. Brodin, M. Cottineau, D. Gully, J.-M. Herbert, P. Keane, C. Labie, J.-C. Molimard, et al. SR146131: A New Potent, Orally Active, and Selective Nonpeptide Cholecystokinin Subtype 1 Receptor Agonist. I: In Vitro Studies J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 742 - 751. [Abstract] [Full Text]

				B. F. Roettger, D. I. Pinon, T. P. Burghardt, and L. J. Miller Regulation of lateral mobility and cellular trafficking of the CCK receptor by a partial agonist Am J Physiol Cell Physiol, March 1, 1999; 276(3): C539 - C547. [Abstract] [Full Text] [PDF]

				D. Ghanekar, E. M. Hadac, E. L. Holicky, and L. J. Miller Differences in Partial Agonist Action at Cholecystokinin Receptors of Mouse and Rat Are Dependent on Parameters Extrinsic to Receptor Structure: Molecular Cloning, Expression and Functional Characterization of the Mouse Type A Cholecystokinin Receptor J. Pharmacol. Exp. Ther., September 1, 1997; 282(3): 1206 - 1212. [Abstract] [Full Text]

				K. Kennedy, V. Gigoux, C. Escrieut, B. Maigret, J. Martinez, L. Moroder, D. Frehel, D. Gully, N. Vaysse, and D. Fourmy Identification of Two Amino Acids of the Human Cholecystokinin-A Receptor That Interact with the N-terminal Moiety of Cholecystokinin J. Biol. Chem., January 31, 1997; 272(5): 2920 - 2926. [Abstract] [Full Text] [PDF]

				B. Ji, A. S. Kopin, and C. D. Logsdon Species Differences between Rat and Mouse CCKA Receptors Determine the Divergent Acinar Cell Response to the Cholecystokinin Analog JMV-180 J. Biol. Chem., June 16, 2000; 275(25): 19115 - 19120. [Abstract] [Full Text] [PDF]