title: Developing dual functional allosteric modulators of GABA(A) receptors.
abstract: Positive modulators at benzodiazepine sites of α2- and α3-containing GABA(A) receptors are believed to be anxiolytic. Negative allosteric modulators of α5-containing GABA(A) receptors enhance cognition. By oocyte two-electrode voltage clamp and subsequent structure-activity relationship studies, we discovered cinnoline and quinoline derivatives that were both positive modulators at α2-/α3-containing GABA(A) receptors and negative modulators at α5-containing GABA(A) receptors. In addition, these compounds showed no functional activity at α1-containing GABA(A) receptors. Such dual functional modulators of GABA(A) receptors might be useful for treating comorbidity of anxiety and cognitive impairments in neurological and psychiatric illnesses.
authors.affiliation: Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA. frankliu8@live.com
authors.forename: Xiaodong F
authors.initials: XF
authors.lastname: Liu
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Chang
authors.forename: Richard Jon
authors.initials: RJ
authors.lastname: Schmiesing
authors.forename: Steven S
authors.initials: SS
authors.lastname: Wesolowski
authors.forename: Katharine S
authors.initials: KS
authors.lastname: Knappenberger
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; D001569:Benzodiazepines / Q000737:chemistry; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011789:Quantum Theory; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D011804:Quinolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C037219:quinoline; C476282:cinnoline