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

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Abstract
Three new analogues of Nα‐hydroxysulfonyl‐[Nle28,31]CCK26‐33 are reported in which the C‐terminal l‐Phe33 residue has been replaced by l‐Leu, d‐Phe or N‐methyl‐l‐Phe.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.