title: Controlled modification of acidity in cholecystokinin B receptor antagonists: N-(1,4-benzodiazepin-3-yl)-N'-[3-(tetrazol-5-ylamino) phenyl]ureas.
abstract: The design, synthesis, and biological activity of a novel series of CCK-B receptor antagonists (1) which incorporate a tetrazol-5-ylamino functionality attached to the phenyl ring of the arylurea moiety of L-365,260 are described. In these compounds, the acidity of the tetrazole was gradually modified by utilization of simple conformational constraints, and X-ray crystallographic data were obtained to support the conformational depenence of the pK(a) of the aminotetrazoles. Compounds to emerge from the present work such as 1f and 2c,d are among the highest affinity and, in the case of 1f, most selective (CCK-A/CCK-B, 37 000) antagonists so far reported for this receptor. The C(5)-cyclohexyl compound 2c (L-736,380) dose-dependently inhibited gastric acid secretion in anesthetized rats (ID(50), 0.064 mg/kg) and ex vivo binding of [(125)I]CCK-8S in BKTO mice brain membranes (ED(50), 1.7 mg/kg) and is one of the most potent acidic CCK-B receptor antagonists yet described.
authors.affiliation: Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Castro
authors.forename: R G
authors.initials: RG
authors.lastname: Ball
authors.forename: H B
authors.initials: HB
authors.lastname: Broughton
authors.forename: M G
authors.initials: MG
authors.lastname: Russell
authors.forename: D
authors.initials: D
authors.lastname: Rathbone
authors.forename: A P
authors.initials: AP
authors.lastname: Watt
authors.forename: R
authors.initials: R
authors.lastname: Baker
authors.forename: K L
authors.initials: KL
authors.lastname: Chapman
authors.forename: A E
authors.initials: AE
authors.lastname: Fletcher
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
authors.forename: W
authors.initials: W
authors.lastname: Ryecroft
authors.forename: V G
authors.initials: VG
authors.lastname: Matassa
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D011869:Radioligand Assay; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001570:Benzodiazepinones; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C058121:L 365260; D012844:Sincalide