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.
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Authors | Eyal Sobol, Boris Yagen, John G Lamb, H Steve White, Bogdan J Wlodarczyk, Richard H Finnell, Meir Bialer |
Journal | Epilepsy research
(Epilepsy Res)
Vol. 73
Issue 1
Pg. 75-84
(Jan 2007)
ISSN: 0920-1211 [Print] Netherlands |
PMID | 16997532
(Publication Type: Journal Article)
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Chemical References |
- Anticonvulsants
- Cyclopropanes
- N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide
- Polyunsaturated Alkamides
- Valproic Acid
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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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