title: Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor.
abstract: Benzodiazepines are allosteric modulators of the GABA(A) receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would have superior therapeutic potential. Herein, we describe the synthesis and biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodiazepine receptor of GABA(A) receptor subtypes. The alpha(2)/alpha(3)-selective partial agonist 42 exhibited potent in vivo activity.
authors.affiliation: Neurogen Corporation, 35 Northeast Industrial Road, Branford, Connecticut 06405, USA. albaugh_pamela@lilly.com
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Albaugh
authors.forename: Lu
authors.initials: L
authors.lastname: Marshall
authors.forename: James
authors.initials: J
authors.lastname: Gregory
authors.forename: Geoff
authors.initials: G
authors.lastname: White
authors.forename: Alan
authors.initials: A
authors.lastname: Hutchison
authors.forename: Phil C
authors.initials: PC
authors.lastname: Ross
authors.forename: Dorothy W
authors.initials: DW
authors.lastname: Gallagher
authors.forename: John F
authors.initials: JF
authors.lastname: Tallman
authors.forename: Matt
authors.initials: M
authors.lastname: Crago
authors.forename: James V
authors.initials: JV
authors.lastname: Cassella
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004594:Electrophysiology; D018755:GABA Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: C468791:9-(3-pyridylmethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydroimidazo(1,2-c)pyrido(3,4-e)pyrimidin-5(6H)-one; D018755:GABA Agonists; D007093:Imidazoles; D008024:Ligands; D011744:Pyrimidinones; D011963:Receptors, GABA-A