Year: 2017
Type: article
Abstract: 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 γ-aminobutyric acid type A (GABAA) receptors. DCUK-OEt was shown to be a positive allosteric modulator (PAM) of GABA currents with α1β2γ2, α1β3γ2, α5β3γ2 and α1β3δ GABAAreceptors, while having no significant PAM effect on αβ receptors or α1β1γ2, α1β2γ1, α4β3γ2 or α4β3δ receptors. DCUK-OEt modulation of α1β2γ2 GABAAreceptors was not blocked by flumazenil. The subunit requirements for DCUK-OEt actions distinguished DCUK-OEt from other currently known modulators of GABA function (e.g., anesthetics, neurosteroids or ethanol). Simulated docking of DCUK-OEt at the GABAAreceptor suggested that its binding site may be at the α + β- subunit interface. In slices of the central amygdala, DCUK-OEt acted primarily on extrasynaptic GABAAreceptors containing the α1 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 GABAAreceptors. 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.
Source: Scientific Reports
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Funders: Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, National Institutes of Health, University of North Carolina at Chapel Hill, Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, National Center for Advancing Translational Sciences
Awards: G1182129601, G1368206816, G1504593296, G1915163810, G1937166206, G2593618960, Alcohol Actions-Molecular Targets on Brain Proteins, Integrative Neuroscience Initiative on Alcoholism, Nezavist a Novel Molecule for Treatment of Alcohol Use Disorder, Integrative Neuroscience Initiative on Alcoholism, Medications for the Treatment of Alcohol Abuse and Dependence and Relapse, Colorado Clinical and Translational Sciences Institute, G8572998776, G9000107746, G9000301818, G9000338494, 9/10 Electrophysiology of Alcohol in Extended Amygdala
OpenAlex ID: W2737658934