Anticonvulsant profile and teratogenicity of N-methyl-tetramethylcyclopropyl carboxamide: a new antiepileptic drug.
OBJECTIVE
The studies presented here represent our efforts to investigate the anticonvulsant activity of N-methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite tetramethylcyclopropyl carboxamide (TMCD) in various animal (rodent) models of human epilepsy, and to evaluate their ability to induce neural tube defects (NTDs) and neurotoxicity.


METHODS
The anticonvulsant activity of M-TMCD and TMCD was determined after intraperitoneal (i.p.) administration to CF#1 mice, and either oral or i.p. administration to Sprague-Dawley rats. The ability of M-TMCD and TMCD to block electrical-, chemical-, or sensory-induced seizures was examined in eight animal models of epilepsy. The plasma and brain concentrations of M-TMCD and TMCD were determined in the CF#1 mice after i.p. administration. The induction of NTDs by M-TMCD and TMCD was evaluated after a single i.p. administration at day 8.5 of gestation in a highly inbred mouse strain (SWV) that is susceptible to valproic acid-induced neural tube defects.


RESULTS
In mice, M-TMCD afforded protection against maximal electroshock (MES)-induced, pentylenetetrazol (Metrazol)-induced, and bicuculline-induced seizures, as well as against 6-Hz "psychomotor" seizures and sound-induced seizures with ED50 values of 99, 39, 81, 51, and 10 mg/kg, respectively. In rats, M-TMCD effectively prevented MES- and Metrazol-induced seizures and secondarily generalized seizures in hippocampal kindled rats (ED50 values of 82, 45, and 39 mg/kg, respectively). Unlike M-TMCD, TMCD was active only against Metrazol-induced seizures in mice and rats (ED50 values of 57 and 52 mg/kg, respectively). Neither M-TMCD nor TMCD was found to induce NTDs in SWV mice.


CONCLUSIONS
The results obtained in this study show that M-TMCD is a broad-spectrum anticonvulsant drug that does not induce NTDs and support additional studies to evaluate its full therapeutic potential.
Isoherranen
Nina
N
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
White
H Steve
HS
Finnell
Richard H
RH
Yagen
Boris
B
Woodhead
José H
JH
Bennett
Gregory D
GD
Wilcox
Karen S
KS
Barton
Matthew E
ME
Bialer
Meir
M
D000161:Acoustic Stimulation; D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001640:Bicuculline; D003292:Convulsants; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004594:Electrophysiology; D004597:Electroshock; D004827:Epilepsy / Q000188:drug therapy* / Q000523:psychology; D007274:Injections, Intraperitoneal; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009436:Neural Tube Defects / Q000139:chemically induced; D010433:Pentylenetetrazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control
C116673:2,2,3,3-tetramethylcyclopropane carboxamide; D000577:Amides; D000927:Anticonvulsants; D003292:Convulsants; D003521:Cyclopropanes; C116674:N-methyl 2,2,3,3-tetramethylcyclopropane carboxamide; D010433:Pentylenetetrazole; D001640:Bicuculline