Derivatives of CCK-(26-32) as cholecystokinin receptor antagonists in guinea pig pancreatic acini.

Abstract

In the present study we synthesized cholecystokinin-(26-32)-amide [CCK-(26-32)-NH2], N-acetyl-cholecystokinin-(26-32) [Ac-CCK-(26-32)], and N-acetyl-cholecystokinin-(26-32)-amide [Ac-CCK-(26-32)-NH2]. None of these peptides altered amylase secretion from dispersed acini prepared from guinea pig pancreas, but each peptide inhibited the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin [CCK-(26-33)]. Half-maximal inhibition of CCK-(26-33)-stimulated amylase secretion occurred with 10 microM CCK-(26-32)-NH2, with 25 microM Ac-CCK-(26-32)-NH2, and with 100 microM Ac-CCK-(26-32). Ac-CCK-(26-32) caused a parallel rightward shift in the dose-response curve for CCK-(26-33)-stimulated amylase secretion. Ac-CCK-(26-32)-NH2 inhibited the stimulation of amylase secretion caused by CCK-(26-33), caerulein, or gastrin-(2-17) but did not alter the stimulation caused by carbachol, bombesin, physalaemin, A23187, vasoactive intestinal peptide, secretin, or 8-bromoadenosine 3',5'-cyclic monophosphate. There was a close correlation between the abilities of derivatives of CCK-(26-32) to inhibit binding of 125I-cholecystokinin (125I-CCK) to pancreatic acini and their abilities to inhibit the stimulation of amylase secretion caused by CCK-(26-33). Half-maximal inhibition of binding of 125I-CCK occurred with 5 microM CCK-(26-32)-NH2, with 7 microM Ac-CCK-(26-32)-NH2, and with 70 microM Ac-CCK-(26-32). These findings indicate that each of the three derivatives of CCK-(26-32) is a specific competitive antagonist of the interaction of cholecystokinin with its cell surface receptors on pancreatic acini.(ABSTRACT TRUNCATED AT 250 WORDS)