Affinity of cholecystokinin receptor antagonists for the gastrin-binding protein

Abstract

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-(1 H-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.