Developing dual functional allosteric modulators of GABA(A) receptors.
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.
Liu
Xiaodong F
XF
Department of Neuroscience Biology, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA. frankliu8@live.com
Chang
Hui-Fang
HF
Schmiesing
Richard Jon
RJ
Wesolowski
Steven S
SS
Knappenberger
Katharine S
KS
Arriza
Jeffrey L
JL
Chapdelaine
Marc J
MJ
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
D006574:Heterocyclic Compounds, 2-Ring; D011804:Quinolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C037219:quinoline; C476282:cinnoline