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new analogues of N alpha-hydroxysulfonyl-[Nle28,31]CCK26-33 are reported in which the C-terminal L-Phe33 residue has been replaced by L-Leu, D-Phe or N-methyl-L-Phe.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.
Sugg
E E
EE
Department of Chemistry, University of Arizona, Tucson.
Serra
M
M
Shook
J E
JE
Yamamura
H I
HI
Burks
T F
TF
Korc
M
M
Hruby
V J
VJ
D000109:Acetylcholine / Q000494:pharmacology; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis*; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D009842:Oligopeptides; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin; D000681:Amylases; D000109:Acetylcholine