Affinity of cholecystokinin receptor antagonists for the gastrin-binding protein.
A 78 kDa gastrin-binding protein is a likely target for the anti-proliferative effects of the cholecystokinin (CCK) receptor antagonists D,L-4-benzamido-N,N-dipropylglutaramic acid (proglumide) and N-4-chlorobenzoyl-L-tryptophan (benzotript) on colorectal carcinoma cell lines [Baldwin, G.S., 1994. Antiproliferative gastrin/cholecystokinin receptor antagonists target the 78-kDa gastrin-binding protein. Proc. Natl. Acad. Sci. USA 91, 7593-7597.]. Definition of the physiological role of the gastrin-binding protein has been hampered by the very low affinity of benzotript for the gastrin-binding protein. Benzotript analogues were therefore tested for their ability to inhibit the binding of iodinated gastrin to the gastrin-binding protein. The affinity of the most potent analogue (the D-isomer of benzotript, CR 665) was similar to the value reported previously for the L-isomer. In order to isolate more potent binding inhibitors, several selective CCK receptor antagonists were also tested as inhibitors of the binding of gastrin to the gastrin-binding protein. The affinity of the most potent binding inhibitor PD 149164 (benzenebutanoic acid, 4-fluoro-!b/-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3 .1. 1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-, [R-(R*,S*)]-) was approximately 10-fold higher than the L-isomer of benzotript. PD 149164 may serve as the lead compound for the future development of more potent and selective gastrin-binding protein inhibitors.
Rorison
K A
KA
Department of Surgery, University of Melbourne, Austin and Repatriation Medical Centre, Austin Campus, Studley Rd., Heidelberg, Australia.
Yang
Z
Z
Baldwin
G S
GS
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000378:metabolism / Q000494:pharmacology; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes; D010084:Oxidation-Reduction; D011377:Proglumide / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011949:Receptors, Cholecystokinin / Q000819:agonists / Q000037:antagonists & inhibitors*; D013552:Swine
D000897:Anti-Ulcer Agents; D001549:Benzamides; D002352:Carrier Proteins; D005227:Fatty Acids; D005755:Gastrins; D007211:Indoles; D009097:Multienzyme Complexes; C103205:PD 149164; D011949:Receptors, Cholecystokinin; D063991:Mitochondrial Trifunctional Protein; D011377:Proglumide; C013841:benzotript; D000218:Adamantane