D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures

doi:10.1016/0920-1211(95)00101-8

Epilepsy Research

Volume 23, Issue 3, April 1996, Pages 211-223

https://doi.org/10.1016/0920-1211(95)00101-8 Get rights and content

Abstract

The anticonvulsant activity of the novel drug D-23129 (N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester) was evaluated in animal models of epileptic seizures. D-23129 was active after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests at nontoxic doses. The compound was active against electrically induced seizures (MES, ED₅₀ rat p.o. = 2.87 mg/kg), against seizures induced chemically by pentylenetetrazole (s.c. PTZ, ED₅₀ mouse p.o. = 13.5 mg/kg), picrotoxin and N-methyl-d-aspartate (NMDA) and in genetic animal model, the DBA/2 mouse. It was not active against seizures induced by bicuculline and strychnine. Motor impairment, evaluated with the rotarod test and by observation in the open field, was minimal at doses showing anticonvulsant activity. D-23129 was very effective in elevating the threshold for electrically and chemically induced seizures. Considering the dose increasing the MES threshold by 50% (TID₅₀ mouse i.p. = 1.6 mg/kg; TID₅₀ rat i.p. = 0.72 mg/kg) and the TD₅₀ obtained in the rotarod test, the protective index of D-23129 is better than that of valproate and phenytoin. During 14 days chronic oral treatment with 15 mg/kg, no development of tolerance was observed. D-23129 thus presents an orally active, safe, broad spectrum anticonvulsant agent, which is structurally unrelated to anticonvulsants currently used. We expect that D-23129 will improve the treatment of refractory seizures in humans.

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We measured the effect of retigabine on MES-induced seizures in rats to determine the efficacy of a dose of 5 mg/kg on neuronal excitability. As a result, retigabine at 5 mg/kg almost suppressed the incidence of MES-induced seizures in rats, consistent with a previous report that retigabine inhibited MES-induced seizures in rats at approximately 5 mg/kg (ED50; 5.1 mg/kg, i.p.) [34]. Our rat TMS system had sufficient sensitivity to detect the modulation of neuronal excitability by lamotrigine and retigabine, which can predict antiepileptic efficacy in the MES model in rats.
Transcranial magnetic stimulation (TMS) is a neurophysiological technique that enables noninvasive evaluation of neuronal excitability in the brain. In the past, a large number of antiepileptic drugs were shown to increase the motor threshold (MT) in clinical TMS studies, suggesting the inhibition of excessive neuronal excitability. To facilitate drug development, the confirmation of similar changes in neurophysiological biomarkers in both preclinical and clinical studies is crucial; however, until now, there have been no data showing the drug efficacies on neuronal excitabilities as measured using TMS in rodents. In this study, we found that the antiepileptic drugs, lamotrigine (10 mg/kg) and retigabine (5 mg/kg), significantly increased the MT in rats using TMS, which is similar to clinical study findings. In addition, we demonstrated that these drugs could inhibit maximal electroshock (MES)-induced seizures in rats when given at the same dose required to be effective in the TMS experiment. These findings suggest that the effects of antiepileptic drugs in our rat TMS system have a similar sensitivity to that of the antiepileptic effects in rats with MES-induced seizures. The measurement of MT in a TMS study may be a noninvasive translational approach for predicting antiepileptic efficacy in drug development.
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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.
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Research reportD-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures

Abstract

Neurosci. Lett.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Intractable epilepsy: Introduction

Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes of their preparation and pharmaceutical compositions containing them

Allgemeine pharmakologische Untersuchungen mit dem Analgetikum Flupirtin

Arzneim.-Forsch./Drug Res.

Chemical protection against ionizing radiation. I. Sampling methods for screening compounds in radiation protection studies with mice

Radiat. Res.

A simplified method of evaluating dose-effect experiments

J. Pharmacol. Exp. Ther.

Do we need novel anti-epileptic drugs?

Br. J. Clin. Pract.

Ralitoline: a reevaluation of anticonvulsant profile and determination of ‘active’ plasma concentrations in comparison with prototype antiepileptic drugs in mice

Epilepsia

Antiepileptic effects of a new drug: D-20443

Epilepsia

Anticonvulsant activity of D-20443

Naunyn-Schmiedenberg's Arch. Pharmacol.

Research report
D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures