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-(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.

• Authors: K A Rorison, Z Yang, G S Baldwin
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 388 Issue 1 Pg. 9-15 (Jan 24 2000) ISSN: 0014-2999 [Print] Netherlands
• PMID: 10657541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Ulcer Agents
• Benzamides
• Carrier Proteins
• Fatty Acids
• Gastrins
• Indoles
• Multienzyme Complexes
• PD 149164
• Receptors, Cholecystokinin
• Mitochondrial Trifunctional Protein
• Proglumide
• benzotript
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Anti-Ulcer Agents (metabolism, pharmacology)
• Benzamides (metabolism, pharmacology)
• Carrier Proteins (antagonists & inhibitors, isolation & purification, metabolism)
• Cells, Cultured
• Fatty Acids (metabolism)
• Fibroblasts (metabolism)
• Gastrins (metabolism)
• Humans
• Indoles (pharmacology)
• Mitochondria (metabolism)
• Mitochondrial Trifunctional Protein
• Multienzyme Complexes
• Oxidation-Reduction
• Proglumide (metabolism, pharmacology)
• Protein Binding
• Receptors, Cholecystokinin (agonists, antagonists & inhibitors)
• Swine