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

Rostock, Angelika; Tober, Christine; Rundfeldt, Chris; Bartsch, Reni; Engel, Jürgen; Polymeropoulos, Emanuele E.; Kutscher, Bernhard; Löscher, Wolfgang; Hönack, Dagmar; White, H.Steve; Wolf, Harold H.

« Previous Next »Epilepsy Research
Volume 23, Issue 3 , Pages 211-223, April 1996

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

Angelika Rostock
- Department of Pharmacology, Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Meissnerstr. 35, D-o1445 Radebeul, Germany
Christine Tober
- Department of Pharmacology, Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Meissnerstr. 35, D-o1445 Radebeul, Germany
Chris Rundfeldt
- Corresponding author.
- Department of Pharmacology, Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Meissnerstr. 35, D-o1445 Radebeul, Germany
Reni Bartsch
- Department of Pharmacology, Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Meissnerstr. 35, D-o1445 Radebeul, Germany
Jürgen Engel
- Department of Pharmacology, Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Meissnerstr. 35, D-o1445 Radebeul, Germany
Emanuele E. Polymeropoulos
- Department of Pharmacology, Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Meissnerstr. 35, D-o1445 Radebeul, Germany
Bernhard Kutscher
- Department of Pharmacology, Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Meissnerstr. 35, D-o1445 Radebeul, Germany
Wolfgang Löscher
- Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany
Dagmar Hönack
- Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany
H.Steve White
- Department of Pharmacology, University of Utah, Salt Lake City, Utah, USA
Harold H. Wolf
- Department of Pharmacology, University of Utah, Salt Lake City, Utah, USA

Received 9 August 1995; accepted 24 November 1995.

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.

Keywords: Complex partial seizure, Carbamazepine, Phenytoin, Phenobarbital, Valproate, Electroshock, Pentylenetetrazole, Seizure threshold