Molecular Pharmacology, Vol 17, 268-274, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Butyryl Derivatives of Cyclic GMP Interfere with the Biological and the Immunological Properties of the Pancreozymin-Gastrin Family of Peptides

¹ Department of Biochemistry and Nutrition and Department of Experimental Surgery, Université Libre de Bruxelles, Medical School, Boulevard de Waterloo, 115, B-1000 Brussels, Belgium

A comparison has been made of the ability of dibutyryl cyclic GMP and parent nucleotides to compete with ¹²⁵I-pancreozymin for binding to rat pancreatic plasma membranes. A parallel study of the inhibitory effects of these nucleotides on the stimulation by the C-terminal octapeptide of pancreozymin on (a) amylase secretion from pancreatic fragments, and (b) adenylate cyclase activity in pancreatic plasma membranes has been conducted. The data suggest a specific, immediate, and full competitive inhibition exerted by dibutyryl cyclic GMP on the binding of peptides of the pancreozymin family (including tetragastrin) to their specific receptors. The presence of a butyryl side chain on the purine base was essential for inhibiting hormone binding and the resulting activation of adenylate cyclase. In addition, the second butyryl side chain on the ribose moiety allowed maximum efficacy. The effects of dibutyryl cyclic GMP did not bear directly on the catalytic subunit of adenylate cyclase, and did not depend on the presence of nucleotide triphosphates. The fast dissociation states evoked by a high degree of occupancy of hormone receptors by pancreozymin analog or by the addition of GTP were not reproduced by dibutyryl cyclic GMP. In general, the biological potencies of dibutyryl cyclic GMP analogs on the exocrine pancreas were proportional to their capacity to be recognized by pancreozymin-gastrin antibodies.

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ACKNOWLEDGMENTS We thank Drs. J. D. Gardner, J. De Graef and M. Svoboda for helpful discussions and criticism.