CHOLECYSTOKININ ANTAGONIST

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The overall goal of this project is to extend previous studies on cholecystokinin (CCK) antagonists by synthesizing a series of compounds, based on promising leads from earlier studies, and to test them for potency in a radioreceptor assay using small cell lung carcinoma cells (SCLC) and in a bioassay for effects on cytosolic calcium using Fura-2- loaded (SCLC) cells. The general approach offered will maximize the potency of antagonist peptides and then make small changes at the carboxy- terminus that have been shown to eliminate agonist activity (with the expectation that receptor binding will be maintained). Previous work in this field has followed two main approaches. Modified benzodiazepine structures have been tested, and the peptide structure of CCK-8 has been modified. Various derivatives have indicated several receptor types, including type A (pancreatic or peripheral), type B (cortal or central), and apparently type C (gastrin). This work will focus on developing antagonists of type B or central CCK receptors. A series of six and seven amino acid compounds will be synthesized. Two cyclized peptides will also be synthesized and studied.