Cholecystokinic activity of Nα-hydroxysulfonyl-[Nle28,31]CCK26-33 analogues modified at the C-terminal residue

Three new analogues of Nα-hydroxysulfonyl-[Nle28,31]CCK26-33 are reported in which the C-terminal l-Phe33 residue has been replaced by l-Leu, d-Phe or N-methyl-l-Phe. Biological evaluation in a series of binding and bioassays demonstrates that both l-stereochemistry and an aromatic side chain at position-33 are essential for full agonist activity. While the l-Leu33 and d-Phe33 analogues had reduced potencies in stimulating contraction of the guinea pig ileum or gall bladder, the d-Phe33 analogue was fourfold selective for the ileum. This latter analogue also exhibited apparent partial agonism in the rat pancreatic amylase release assay. The N-methyl-l-Phe33 analogue was almost equipotent to the parent analogue in all bioassays, suggesting that this modification might be useful for introducing enzymatic stability in CCK analogues.