Journal of Translational Neurosciences

Inhibition of EtOH-induced GABAAR potentiation as a Novel mechanism for the treatment of Alcohol Use Disorder

Current pharmacotherapies for the treatment of alcohol use disorder are largely ineffective and/or associated with major side effects. There are currently no treatment options that target the direct neurological effects of ethanol, despite this mechanism of pharmacotherapy demonstrating efficacy in the treatment of opiate use disorder. Dihydromyricetin (DHM) is a natural flavonoid that could provide a link to the development of medications targeting ethanol-induced intoxication, through interaction with GABAA receptors. Dihydromyricetin demonstrated remarkable potential in preclinical studies in rats. For instance, dihydromyricetin (IP administration) demonstrated efficacy at counteracting EtOH intoxication, reducing voluntary EtOH intake, preventing EtOH-induced plasticity of GABAARs and withdrawal symptoms, and preventing physiological effects of fetal alcohol syndrome. Evidence indicates that the mechanism is linked to inhibition of ethanol-induced GABAAR potentiation and GABAAR positive allosteric modulation through mutually exclusive binding with imidazobenzodiazepines. Despite this promising bioactivity, inadequate pharmacokinetic properties, prevent the effective clinical use of DHM for AUD. Thus, the aim of this study is to determine the pharmacophore of this promising bioactivity to enable lead optimization. Our work has included the design of synthesis of dihydromyricetin analogs that explored structure activity relationships utilizing patch-clamp recordings in Xenopus oocytes expressing α5ß32 GABAARs, and molecular modelling studies in the benzodiazepine binding site of α1β2γ2 GABAARs. The results of our studies have provided insight into necessary functional groups of dihydromyricetin for GABAAR activity. This study has also led to the identification of a novel and chemically stable derivative of dihydromyricetin that is a GABAAR positive allosteric modulator. Our findings highlight the potential for optimization of dihydromyricetin GABAAR activity, forging a path towards the development of a GABAAR positive modulator and inhibitor of ethanol-induced GABAAR potentiation, as a novel and effective mechanism for the treatment of AUD.

Eileen Carry