title: Development and SAR of functionally selective allosteric modulators of GABAA receptors.
abstract: Positive modulators at the benzodiazepine site of α2- and α3-containing GABA(A) receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABA(A) receptors and that show no functional activity at α1-containing GABA(A) receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABA(A) receptors, while simultaneously neutral antagonists at α1-containing GABA(A) receptors, is described. Such functionally selective modulators of GABA(A) receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.
authors.affiliation: Department of Chemistry, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Alhambra
authors.forename: Chris
authors.initials: C
authors.lastname: Becker
authors.forename: Timothy
authors.initials: T
authors.lastname: Blake
authors.forename: Amy Hui-Fang
authors.initials: AH
authors.lastname: Chang
authors.forename: James R
authors.initials: JR
authors.lastname: Damewood
authors.forename: Thalia
authors.initials: T
authors.lastname: Daniels
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Dembofsky
authors.forename: David A
authors.initials: DA
authors.lastname: Gurley
authors.forename: James E
authors.initials: JE
authors.lastname: Hall
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Herzog
authors.forename: Carey L
authors.initials: CL
authors.lastname: Horchler
authors.forename: Cyrus J
authors.initials: CJ
authors.lastname: Ohnmacht
authors.forename: Richard Jon
authors.initials: RJ
authors.lastname: Schmiesing
authors.forename: Adam
authors.initials: A
authors.lastname: Dudley
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ribadeneira
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Knappenberger
authors.forename: Carla
authors.initials: C
authors.lastname: Maciag
authors.forename: Mark M
authors.initials: MM
authors.lastname: Stein
authors.forename: Maninder
authors.initials: M
authors.lastname: Chopra
authors.forename: Xiaodong F
authors.initials: XF
authors.lastname: Liu
authors.forename: Edward P
authors.initials: EP
authors.lastname: Christian
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Arriza
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Chapdelaine
mesh_terms: D000494:Allosteric Regulation; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry; D058787:GABA-A Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D058787:GABA-A Receptor Antagonists; D006574:Heterocyclic Compounds, 2-Ring; D011804:Quinolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C037219:quinoline; C476282:cinnoline