N-terminal fragments of CCK-(26-33) as cholecystokinin receptor antagonists in guinea pig pancreatic acini

Abstract

In the present study we synthesized different N-terminal fragments and analogues of the C-terminal octapeptide of cholecystokinin [CCK-(26-33)] and examined their actions on dispersed acini prepared from guinea pig pancreas. None of the N-terminal fragments or analogues altered basal amylase release. Analogues of CCK-(26-32), CCK-(26-31), and CCK-(26-30) inhibited CCK-(26-33)-stimulated amylase, and there was a close correlation between the ability of an analogue to inhibit stimulated amylase and the analogue's ability to inhibit binding of 125I-cholecystokinin. N-acetyl-CCK-(26-29)-amide at concentrations as high as 100 microM did not inhibit CCK-(26-33)-stimulated amylase release or binding of 125I-CCK. For those analogues that antagonized CCK-(26-33)-stimulated amylase release the antagonism was of the competitive type and was specific for those secretagogues that interact with the cholecystokinin receptor. Removing the C-terminal amide from N-acetyl-CCK-(26-31)-amide caused a 10-fold decrease in the inhibitory potency, whereas removing the C-terminal amide from N-acetyl-CCK-(26-30)-amide did not alter the inhibitory potency of the peptide. Removing the sulfate ester from the tyrosine residue in position 27 of N-acetyl-CCK-(26-31) did not alter the inhibitory potency of the peptide, whereas removing the sulfate ester from the tyrosine residue in position 27 of N-acetyl-(26-30) caused a three- to fivefold decrease in the inhibitory potency of the peptide.(ABSTRACT TRUNCATED AT 250 WORDS)