The novel dual-mechanism Kv7 potassium channel/TSPO receptor activator GRT-X is more effective than the Kv7 channel opener retigabine in the 6-Hz refractory seizure mouse model

Abstract

Epilepsy, one of the most common and most disabling neurological disorders, is characterized by spontaneous recurrent seizures, often associated with structural brain alterations and cognitive and psychiatric comorbidities. In about 30% of patients, the seizures are resistant to current treatments; so more effective treatments are urgently needed. Among the ∼30 clinically approved antiseizure drugs, retigabine (ezogabine) is the only drug that acts as a positive allosteric modulator (or opener) of voltage-gated Kv7 potassium channels, which is particularly interesting for some genetic forms of epilepsy. Here we describe a novel dual-mode-of-action compound, GRT-X (N-[(3-fluorophenyl)-methyl]-1-(2-methoxyethyl)-4-methyl-2-oxo-(7-trifluoromethyl)-1H-quinoline-3-carboxylic acid amide) that activates both Kv7 potassium channels and the mitochondrial translocator protein 18 kDa (TSPO), leading to increased synthesis of brain neurosteroids. TSPO activators are known to exert anti-inflammatory, neuroprotective, anxiolytic, and antidepressive effects, which, together with an antiseizure effect (mediated by Kv7 channels), would be highly relevant for the treatment of epilepsy. This prompted us to compare the antiseizure efficacy of retigabine and GRT-X in six mouse and rat models of epileptic seizures, including the 6-Hz model of difficult-to-treat focal seizures. Furthermore, the tolerability of the two compounds was compared in mice and rats. Potency comparisons were based on both doses and peak plasma concentrations. Overall, GRT-X was more effective than retigabine in three of the six seizure models used here, the most important difference being the high efficacy in the 6-Hz (32 mA) seizure model in mice. Based on drug plasma levels, GRT-X was at least 30 times more potent than retigabine in the latter model. These data indicate that GRT-X is a highly interesting novel anti-seizure drug with a unique (first-in-class) dual-mode mechanism of action.