Boc-CCK-4 derivatives containing side-chain ureas as potent and selective CCK-a receptor agonists.
Novel Boc-CCK-4 derivatives were communicated recently as having high potency and selectivity for the CCK-A receptor (Shiosaki et al. J. Med. Chem. 1990, 33, 2950-2952). While Boc-CCK-4 binds selectively to the CCK-B receptor, replacement of the methionine with an N epsilon-substituted lysine dramatically reversed receptor selectivity, leading to the development of this novel series of tetrapeptides. A detailed structure-activity analysis of a series of urea-substituted tetrapeptides, represented by the general structure Boc-Trp-Lys(N epsilon-CO-NHR)-Asp-Phe-NH2, revealed that a number of substituted phenyl, naphthyl, and aliphatic urea residues in the lysine side chain yielded potent and selective CCK-A ligands. These tetrapeptides elicit full agonist responses in stimulating pancreatic amylase release that are effectively blocked by a selective CCK-A receptor antagonist. Conversion of the urea to a thiourea significantly reduced CCK-A binding potency as did replacement of the lysine with the homologous ornithine or homolysine. Tetrapeptides that were partial agonists (less than 80% efficacy) in phosphoinositide (PI) hydrolysis relative to CCK-8 did not exhibit high-dose inhibition of amylase secretion in guinea pig acini.
Shiosaki
K
K
Neuroscience Research Division, Department 47H, Abbott Laboratories, Abbott Park, Illinois 60064.
Lin
C W
CW
Kopecka
H
H
Tufano
M D
MD
Bianchi
B R
BR
Miller
T R
TR
Witte
D G
DG
Nadzan
A M
AM
D000595:Amino Acid Sequence; D000681:Amylases / Q000378:metabolism; D000818:Animals; D006168:Guinea Pigs; D006868:Hydrolysis; D008969:Molecular Sequence Data; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D010716:Phosphatidylinositols / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000187:drug effects*; D013758:Tetragastrin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000737:chemistry*
D010716:Phosphatidylinositols; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; C063051:butyloxycarbonyl-tryptophyl-methionyl-aspartyl-phenylalaninamide; D014508:Urea; D000681:Amylases