Cyclic nucleotide antagonists of cholecystokinin: structural requirements for interaction with the cholecystokinin receptor.

Previously, we have found that, in pancreatic acini, butyryl derivatives of cGMP antagonize the action of cholecystokinin by inhibiting binding of the peptide to its membrane receptors. In the present study, we found that derivatives of cAMP and cIMP can also inhibit binding of cholecystokinin as well as its actions on acinar cell function. Moreover, the inhibition caused by cyclic nucleotide derivatives did not require the presence of a butyryl moiety, because certain 8-bromo-cyclic nucleotides also inhibited the interaction of cholecystokinin with its receptors. Cyclic nucleotide derivatives can also increase pancreatic enzyme secretion; however, for the various cyclic nucleotides tested, there was no apparent correlation between their abilities to stimulate enzyme secretion and their abilities to antagonize the actions of cholecystokinin. Finally, cyclic nucleotide derivatives also inhibited binding of 125I-cholecystokinin to antibodies that were specific for the biologically active, C-terminal region of cholecystokinin. Thus, certain cyclic nucleotide derivatives possess a conformational structural which resembles that of the biologically active portion of cholecystokinin, and this structural similarity accounts for the abilities of these nucleotide derivatives to interact with cholecystokinin receptors and, by so doing, to inhibit the action of cholecystokinin on its target tissues.