Structure-function studies of N-acyl derivatives of tryptophan that function as specific cholecystokinin receptor antagonists.
Benzotript, N-p-chlorobenzoyl-L-tryptophan, is a specific cholecystokinin receptor antagonist. In the present study we used dispersed pancreatic acini to examine tryptophan as well as several different N-acyl derivatives of tryptophan for their abilities to function as cholecystokinin receptor antagonists. L-Tryptophan, D-tryptophan as well as each acyl derivative tested inhibited cholecystokinin-stimulated amylase secretion and outflux of 45Ca and there was a good correlation between the ability of a particular agent to inhibit the action of cholecystokinin on acinar function and its ability to inhibit binding of 125I-labeled cholecystokinin to pancreatic acini. Results with butyloxycarbonyl-L-tryptophan indicated that the inhibition of the action of cholecystokinin caused by L-tryptophan and various acyl derivatives is specific, competitive and fully reversible. In functioning as a cholecystokinin receptor antagonist the relative potencies of the agents tested were: carbobenzoxy-L-tryptophan greater than benzotript greater than benzoyl-L-tryptophan = butyloxycarbonyl-L-tryptophan greater than acetyl-L-tryptophan greater than L-tryptophan. In inhibiting the actions of cholecystokinin, native as well as N-acyl derivatives of D-tryptophan were equipotent with the corresponding compound containing L-tryptophan. Although L-tryptophan inhibited the actions of cholecystokinin, L-phenylalanine, L-methionine or L-aspartic acid, even when tested at concentrations as high as 3 mM, did not alter the action of cholecystokinin on pancreatic acini. The antagonism of the actions of cholecystokinin was not restricted to N-acyl derivatives of L-tryptophan because butyloxycarbonyl-L-methionine and butyloxycarbonyl-L-phenylalanine but not butyloxycarbonyl-L-aspartic acid also antagonized the actions of cholecystokinin. These results demonstrate that both the nature of the N-acyl group and the amino acid residue are important determinants of the affinity of the antagonist for the cholecystokinin receptor. For derivatives of L-tryptophan, the more hydrophobic the N-acyl moiety, the greater the affinity of the derivative for the cholecystokinin receptor.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002766:Cholecystokinin / Q000378:metabolism*; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D010179:Pancreas / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D011949:Receptors, Cholecystokinin; D012844:Sincalide / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D011956:Receptors, Cell Surface; D011949:Receptors, Cholecystokinin; D014364:Tryptophan; D002766:Cholecystokinin; D012844:Sincalide; D002118:Calcium