Interaction of tryptophan-modified analogues of cholecystokinin-octapeptide with cholecystokinin receptors on pancreatic acini.
None of six different tryptophan-modified analogues of the C-terminal octapeptide of cholecystokinin differed from the unaltered peptide in terms of their efficacies for stimulating amylase secretion from dispersed acini prepared from guinea-pig pancreas. Replacement of hydrogen with fluorine in position 5 or 6 on the indole ring of the tryptophan residue did not alter the potency with which the peptide stimulated amylase secretion; however, replacement of hydrogen by fluorine in positions 4, 5, 6 and 7 of the indole ring, or modifying or replacing the indole nitrogen caused a 30- to 300-fold decrease in potency. Changes in the ability of the peptide to inhibit binding of 125I-labeled cholecystokinin. Our findings indicate that reducing the ability of the tryptophan residue to donate electrons produced a greater decrease in the affinity of the peptide for cholecystokinin receptors than did abolishing the ability of tryptophan to form hydrogen bonds, and modification that altered both abilities caused a greater decrease in affinity than did modification of only one ability. Finally, in the tryptophan residues of cholecystokinin octapeptide, tetrafluorination of the indole ring or replacing the indole nitrogen by oxygen reduced the ability of the peptide to cause residual stimulation of enzyme secretion, probably by accelerating the rate at which bound peptide dissociated from its receptors when the acini were washed and resuspended in fresh incubation solution.
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000681:Amylases / Q000378:metabolism*; D000818:Animals; D002766:Cholecystokinin / Q000494:pharmacology*; D006168:Guinea Pigs; D006860:Hydrogen Bonding; D008297:Male; D010179:Pancreas / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011949:Receptors, Cholecystokinin; D012844:Sincalide; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism / Q000494:pharmacology*
D000596:Amino Acids; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D011949:Receptors, Cholecystokinin; D014364:Tryptophan; D002766:Cholecystokinin; D000681:Amylases; D012844:Sincalide