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Title: Affinity of cholecystokinin receptor antagonists for the gastrin-binding protein.
Austin Authors: Rorison, K A;Yang, Z;Baldwin, Graham S
Affiliation: Department of Surgery, University of Melbourne, Austin and Repatriation Medical Centre, Austin Campus, Studley Rd., Heidelberg, Australia
Issue Date: 24-Jan-2000
Publication information: European Journal of Pharmacology; 388(1): 9-15
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.
Gov't Doc #: 10657541
Journal: European Journal of Pharmacology
Type: Journal Article
Subjects: Adamantane.analogs & derivatives.pharmacology
Anti-Ulcer Agents.metabolism.pharmacology
Carrier Proteins.antagonists & inhibitors.isolation & purification.metabolism
Cells, Cultured
Fatty Acids.metabolism
Mitochondrial Trifunctional Protein
Multienzyme Complexes
Protein Binding
Receptors, Cholecystokinin.agonists.antagonists & inhibitors
Appears in Collections:Journal articles

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