title: Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger".
abstract: Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.
authors.affiliation: Department of Medicinal Chemistry, Glaxo Wellcome, Research Triangle Park, North Carolina 27709, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Aquino
authors.forename: D R
authors.initials: DR
authors.lastname: Armour
authors.forename: J M
authors.initials: JM
authors.lastname: Berman
authors.forename: L S
authors.initials: LS
authors.lastname: Birkemo
authors.forename: R A
authors.initials: RA
authors.lastname: Carr
authors.forename: D K
authors.initials: DK
authors.lastname: Croom
authors.forename: M
authors.initials: M
authors.lastname: Dezube
authors.forename: R W
authors.initials: RW
authors.lastname: Dougherty
authors.forename: G N
authors.initials: GN
authors.lastname: Ervin
authors.forename: M K
authors.initials: MK
authors.lastname: Grizzle
authors.forename: J E
authors.initials: JE
authors.lastname: Head
authors.forename: G C
authors.initials: GC
authors.lastname: Hirst
authors.forename: M K
authors.initials: MK
authors.lastname: James
authors.forename: M F
authors.initials: MF
authors.lastname: Johnson
authors.forename: L J
authors.initials: LJ
authors.lastname: Miller
authors.forename: K L
authors.initials: KL
authors.lastname: Queen
authors.forename: T J
authors.initials: TJ
authors.lastname: Rimele
authors.forename: D N
authors.initials: DN
authors.lastname: Smith
authors.forename: E E
authors.initials: EE
authors.lastname: Sugg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D001067:Appetite Depressants; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines