Novel Molecule Exhibiting Selective Affinity for GABA(A) Receptor Subtypes

作者：Borghese Cecilia M; Herman Melissa; Snell Lawrence D; Lawrence Keri J; Lee Hyun Young; Backos Donald S; Vanderlinden Lauren A; Harris R Adron; Roberto Marisa; Hoffman Paula L; Tabakoff Boris^*

来源：Scientific Reports, 2017, 7(1): 6230.

DOI：10.1038/s41598-017-05966-x

Aminoquinoline derivatives were evaluated against a panel of receptors/channels/transporters in radioligand binding experiments. One of these derivatives (DCUK-OEt) displayed micromolar affinity for brain gamma-aminobutyric acid type A (GABA(A)) receptors. DCUK-OEt was shown to be a positive allosteric modulator (PAM) of GABA currents with alpha 1 beta 2 gamma 2, alpha 1 beta 3 gamma 2, alpha 5 beta 3 gamma 2 and alpha 1 beta 3 delta GABA(A) receptors, while having no significant PAM effect on alpha beta receptors or alpha 1 beta 1 gamma 2, alpha 1 beta 2 gamma 1, alpha 4 beta 3 gamma 2 or alpha 4 beta 3 delta receptors. DCUK-OEt modulation of alpha 1 beta 2 gamma 2 GABA(A) receptors was not blocked by flumazenil. The subunit requirements for DCUK-OEt actions distinguished DCUK-OEt from other currently known modulators of GABA e.g., anesthetics, neurosteroids or ethanol). Simulated docking of DCUK-OEt at the GABA(A) receptor suggested that its binding site may be at the alpha+beta- subunit interface. In slices of the central amygdala, DCUK-OEt acted primarily on extrasynaptic GABA(A) receptors containing the alpha 1 subunit and generated increases in extrasynaptic "tonic" current with no significant effect on phasic responses to GABA. DCUK-OEt is a novel chemical structure acting as a PAM at particular GABA(A) receptors. Given that neurons in the central amygdala responding to DCUK-OEt were recently identified as relevant for alcohol dependence, DCUK-OEt should be further evaluated for the treatment of alcoholism.

• 出版日期2017-7-24