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Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug, N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide.

Abstract
N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (OM-TMCD) is a methoxyamide derivative of a cyclopropyl analogue of valproic acid (VPA). The structural considerations used in the design of OM-TMCD were aimed to enhance OM-TMCD anticonvulsant potency (compared to VPA) and to prevent VPA's two life-threatening side effects, i.e., induction of neural tube defects (NTDs) and hepatotoxicity. Following i.p. administration to rats OM-TMCD demonstrated a broad spectrum of anticonvulsant activity and showed better potency than VPA in the maximal electroshock seizure and subcutaneous pentylenetetrazole tests as well as in the hippocampal kindling model. OM-TMCD was inactive in the mouse 6-Hz test at 100 mg/kg dose. Teratogenicity studies performed in a SWV/Fnn-mouse model for VPA-induced-exencephaly showed that on the equimolar basis OM-TMCD possesses the same fetal toxicity and ability to induce NTDs as VPA, but since OM-TMCD is a much more potent anticonvulsant its activity/exencephaly formation ratio appears to be much more beneficial than that of VPA. OM-TMCD was found to be non-mutagenic and non-pro-mutagenic in the Ames test. It showed a beneficial pharmacokinetic profile in rats, having a high oral bioavailability of 75% and satisfactory values of clearance and volume of distribution. These results support further studies to fully characterize the therapeutic potential of OM-TMCD.
AuthorsEyal Sobol, Boris Yagen, John G Lamb, H Steve White, Bogdan J Wlodarczyk, Richard H Finnell, Meir Bialer
JournalEpilepsy research (Epilepsy Res) Vol. 73 Issue 1 Pg. 75-84 (Jan 2007) ISSN: 0920-1211 [Print] Netherlands
PMID16997532 (Publication Type: Journal Article)
Chemical References
  • Anticonvulsants
  • Cyclopropanes
  • N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide
  • Polyunsaturated Alkamides
  • Valproic Acid
Topics
  • Abnormalities, Drug-Induced (etiology)
  • Animals
  • Anticonvulsants (adverse effects, pharmacokinetics, pharmacology)
  • Cyclopropanes (adverse effects, pharmacokinetics, pharmacology)
  • Female
  • Male
  • Mice
  • Mutagenesis (drug effects)
  • Neural Tube Defects (chemically induced)
  • Polyunsaturated Alkamides (adverse effects, pharmacokinetics, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Seizures (prevention & control)
  • Valproic Acid (analogs & derivatives)

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