title: A second generation of non-peptide cholecystokinin receptor antagonists and their possible therapeutic potential.
abstract: The profile of an acidic series of benzodiazepine CCK-B receptor antagonists is described. The tetrazolyl urea derivative L-368,935 had high affinity (CCK-B IC50 0.1 nM) and was one of the most selective (CCK-B/CCK-A 10,000) CCK-B antagonists known. L-368,935 was a CCK-B antagonist with high affinity on the rat ventromedial hypothalamic slice preparation (Kb 0.6 nM) and also blocked pentagastrin-induced calcium mobilization in GH3 cells. L-368,935 had potent in vivo activity and antagonized pentagastrin-induced gastric acid secretion in the anesthetized rat and CCK-8S-induced aspartate release using microdialysis in the striatum of conscious rats. Activity within the central nervous system was confirmed by a mouse ex vivo binding assay and by direct measurement of the compound within the central nervous system using an HPLC assay. A second generation of CCK-B receptor antagonists such as L-368,935 will be important in determining the therapeutic potential of this class of compound in man.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Department of Biochemistry, Harlow, Essex, England.
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Chapman
authors.forename: A
authors.initials: A
authors.lastname: Fletcher
authors.forename: J A
authors.initials: JA
authors.lastname: Kemp
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: K
authors.initials: K
authors.lastname: Scholey
authors.forename: E C
authors.initials: EC
authors.lastname: Mellin
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology* / Q000627:therapeutic use*; D015195:Drug Design; D015394:Molecular Structure; D011720:Pyrazoles / Q000494:pharmacology*; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines