Preclinical evaluation of 2,2,3,3-tetramethylcyclopropanecarbonyl-urea, a novel, second generation to valproic acid, antiepileptic drug.
2,2,3,3-Tetramethylcyclopropanecarbonylurea (TMCU) is an amide derivative of a tetramethylcyclopropyl analogue of valproic acid (VPA), one of the leading antiepileptic drugs. Structural considerations used in the design of TMCU aimed to enhance the anticonvulsant potency of VPA and to prevent its two life-threatening side effects; i.e., teratogenicity and hepatotoxicity. The anticonvulsant activity of TMCU was evaluated in the MES, scMet, 6-Hz, scBic and scPic tests, and also in the hippocampal kindling model of partial seizures and lamotrigine-resistant amygdala kindling model of therapy-resistant seizures. Minimal motor impairment was determined using the rotorod test in mice and the positional sense test, muscle tone test, and gait and stance test in rats. The antinociceptive effect of TMCU was evaluated in the mouse formalin model of acute-tonic pain. The molecular mechanisms of action of TMCU were investigated in electrophysiological studies using the whole-cell patch-clamp technique. Teratogenicity studies were performed in a SWV/Fnn-mouse model of VPA-induced teratogenicity. TMCU hepatotoxicity was evaluated following 1-week intraperitoneal and oral administration of 50, 250 and 500 mg/kg doses to rats. In the hepatotoxicity study the blood levels of TMCU were evaluated at day 1 and day 7 of the treatment. TMCU mutagenicity was evaluated in the Ames test.
Sobol
Eyal
E
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Yagen
Boris
B
Steve White
H
H
Wilcox
Karen S
KS
Lamb
John G
JG
Pappo
Orit
O
Wlodarczyk
Bogdan J
BJ
Finnell
Richard H
RH
Bialer
Meir
M
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003521:Cyclopropanes / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D006801:Humans; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test / Q000379:methods; D012640:Seizures / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D014508:Urea / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
C488794:2,2,3,3-tetramethylcyclopropanecarbonylurea; D000927:Anticonvulsants; D003521:Cyclopropanes; D014635:Valproic Acid; D014508:Urea