Jordi Serrats, Krishna C Vadodaria, William Brubaker, Melissa Barker-Haliski, H Steve White, Alexis Evrard, Corinne Roucard, Eve Taylor, Kimberly E Vanover, Stephen Cunningham, Vikram Sudarsan, Michael A Rogawski
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引用次数: 0
Abstract
Objective: γ-Aminobutyric acid type A (GABAA) receptor positive allosteric modulators (PAMs) that lack α-subunit selectivity, including benzodiazepines such as diazepam, exhibit antiseizure actions in animal models and in humans. ENX-101 is a deuterated analog of the ⍺2,3,5-selective GABAA receptor PAM L-838,417. The purpose of this study was to characterize the α-subunit selectivity of ENX-101 and evaluate its antiseizure potential in preclinical seizure and epilepsy models.
Methods: ENX-101 potentiation of GABA chloride current responses in cells expressing recombinant GABAA receptors were evaluated using an automated patch clamp assay. Antiseizure effects of ENX-101 were examined in the mouse 6 Hz test at 32 and 44 mA, amygdala kindled rats, and Genetic Absence Epilepsy Rat from Strasbourg (GAERS).
Results: ENX-101 displayed partial PAM activity with respect to diazepam at GABAA receptors containing α2, α3, or α5 subunits but did not enhance GABA responses of GABAA receptors containing α1 subunits. ENX-101 (30, 100, and 300 mg/kg, i.p.) and diazepam protected most animals in the 6 Hz model at 32 mA but was less effective at 44 mA. In amygdala kindled rats, ENX-101 (1-100 mg/kg, p.o.) reduced behavioral seizure severity and afterdischarge duration in a dose-dependent manner. ENX-101 (0.075-100 mg/kg, p.o.) caused dose-dependent, persistent (>130 min) inhibition of spontaneous spike-and-wave discharges (SWDs) in GAERS, whereas diazepam transiently inhibited discharges. ENX-101 did not cause motor impairment, as measured by performance in the rotarod assay.
Significance: ENX-101 is an α2,α3,α5-selective GABAA receptor PAM that has high potency and partial efficacy. The drug is highly effective in rodent seizure and epilepsy models. ENX-101 is most potent in the GAERS model of absence epilepsy, and active in the 6 Hz model and amygdala kindled rats. These results demonstrate that a partial, subtype-selective GABAA receptor PAM has activity in translationally validated preclinical epilepsy screening models. Clinical evaluation of ENX-101 as a treatment for focal and generalized epilepsies is warranted.
期刊介绍：
Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.
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