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

Three new analogues of N alpha-hydroxysulfonyl-[Nle28,31]CCK26-33 are reported in which the C-terminal L-Phe33 residue has been replaced by L-Leu, D-Phe or N-methyl-L-Phe.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

Synthesis and biological evaluation of N alpha-hydroxysulfonyl-[Nle28,31]-CCK26-33.

Two analogues of [Nle28,31]-CCK26-33 containing an N-terminal acetyl or N-terminal hydroxysulfonyl moiety were prepared and characterized. Both analogues were equipotent to native CCK26-33 in four bioassays, demonstrating that N-terminal sulfation of CCK26-33 analogues is compatible with full biological activity