Characterization of two novel cholecystokinin tetrapeptide (30-33) analogues, A-71623 and A-70874, that exhibit high potency and selectivity for cholecystokinin-A receptors.
Based on their relative affinities for cholecystokinin octapeptide (26-33) (CCK-8), cholecystokinin tetrapeptide (30-33) (CCK-4), desulfated CCK-8, and gastrin, cholecystokinin (CCK) receptors have been classified as CCK-A (alimentary) and CCK-B (brain). Selective nonpeptide antagonists of CCK-A and CCK-B receptors, as well as highly selective CCK-A and CCK-B peptide agonists, have been described. We report here the characterization of two novel CCK-4-based peptides, A-71623 and A-70874. In radioligand binding assays, the IC50 values for A-71623 and A-70874 were 3.7 and 4.9 nM in guinea pig pancreas (CCK-A) and 4500 and 710 nM in cerebral cortex (CCK-B), respectively. Both were agonists in stimulating pancreatic amylase release, and their stimulatory effects were potently inhibited by the CCK-A antagonist L-364,718. A-71623 was a full agonist and A-70874 was a partial agonist (approximately 80%) in stimulating phosphoinositide breakdown in pancreas. Both peptides also were potent agonists in stimulating CCK-A receptors in the ileum. They were, however, weak and behaved as partial agonists in calcium studies in NCI-H345 cells, which possess CCK-B/gastrin receptors. In guinea pig gastric glands, the affinities of A-71623 and A-70874 for the CCK-B/gastrin receptor were 11 and 1.6 microM, respectively. These results demonstrate that A-71623 and A-70874 are potent and selective agonists at CCK-A receptors. The preferential interaction of these novel CCK-4 analogs with CCK-A receptors is in contrast to other CCK-4-based peptides, which are primarily selective for CCK-B receptors. In addition, A-71623 and A-70874 are the first two examples of potent CCK-A agonists that do not contain a tyrosine residue whose sulfation is required for potent CCK-A agonist activity of larger peptides.
Lin
C W
CW
Neuroscience Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500.
Shiosaki
K
K
Miller
T R
TR
Witte
D G
DG
Bianchi
B R
BR
Wolfram
C A
CA
Kopecka
H
H
Craig
R
R
Wagenaar
F
F
Nadzan
A M
AM
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D002766:Cholecystokinin / Q000737:chemistry / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D012636:Secretory Rate / Q000187:drug effects; D013329:Structure-Activity Relationship; D013758:Tetragastrin / Q000031:analogs & derivatives* / Q000378:metabolism
D009842:Oligopeptides; D010716:Phosphatidylinositols; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; C066278:A 71623; C067892:A 70874; D002766:Cholecystokinin; D000681:Amylases