Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model of neuropathic pain

Winkler, Ilan; Sobol, Eyal; Yagen, Boris; Steinman, Amir; Devor, Marshall; Bialer, Meir

doi:10.1016/j.neuropharm.2005.06.008

Cited by 30 publications

(46 citation statements)

References 47 publications

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“…37,40 We recently discovered that MTMCD and TMCU both possess an antiallodynic activity in the rat spinal nerve ligation (SNL) model for neuropathic pain, and are about 7 and 1.5 times more potent than VPA, respectively. 24 The MTMCD in the SNL model was equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. 24 In another study, MTMCD was found to be equipotent to VPA and lithium in various models for bipolar disorders.…”

Section: Derivatives Of Tmcamentioning

confidence: 95%

“…24 The MTMCD in the SNL model was equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. 24 In another study, MTMCD was found to be equipotent to VPA and lithium in various models for bipolar disorders. 41 Thus, the 2,2,3,3-tetramethylcyclopropane amides MTMCD and TMCU have the potential to become new antiepileptics and CNS drugs as the second generation of VPA.…”

Section: Derivatives Of Tmcamentioning

confidence: 95%

“…[18][19][20][21] Designing substituted aliphatic and alicyclic VPA analogues and ␣ and ␤ substituted VPA derivatives (amides) to block the formation of these two metabolites should prevent, or at least minimize, the VPA-induced hepatotoxicity. [22][23][24] Structure-activity relationship studies mapped the structural elements of the VPA molecules responsible for the anticonvulsant activity. 25 Subsequent studies showed that constitutional isomers of VPA, such as valnoctic acid (VCA), propylisopropyl acetic acid (PIA), or diisopropylacetic acid (DIA), were less active as anticonvulsants than VPA.…”

Section: The Second Generation To Valproic Acid (Vpa)mentioning

confidence: 99%

“…[6][7][8]36 The TMCA showed low anticonvulsant activity and did not demonstrate separation between its anticonvulsant activity and neurotoxicity in rodents. 24 However, the amide derivatives of TMCA, 2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD ; FIG. 1), N-methyl-TMCD (MTMCD), and 2,2,3,3-tetramethylcyclopropylcarbonylurea (TMCU ; FIG.…”

Section: Derivatives Of Tmcamentioning

confidence: 99%

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Valproic Acid: Second Generation

2007

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Summary:The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become secondgeneration VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.

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Section: Derivatives Of Tmcamentioning

confidence: 95%

Section: Derivatives Of Tmcamentioning

confidence: 95%

Section: The Second Generation To Valproic Acid (Vpa)mentioning

confidence: 99%

Section: Derivatives Of Tmcamentioning

confidence: 99%

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Valproic Acid: Second Generation

2007

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“…The cyclopropyl VPA analog TMCA and its amide derivatives TMCD, MTMCD, and TMCU all possess anticonvulsant activity in rodent models (Isoherranen et al, 2003;Sobol et al, 2004;Winkler et al, 2005b). Neither TMCA, TMCD, nor TMCU showed an effect on growth cone morphology at concentrations of 3 mM, and they were toxic at higher concentrations (Fig.…”

Section: Second Generation Vpa As Potential Mood Stabilizers 887mentioning

confidence: 97%

The Effects of Central Nervous System-Active Valproic Acid Constitutional Isomers, Cyclopropyl Analogs, and Amide Derivatives on Neuronal Growth Cone Behavior

Shimshoni

Dalton²,

Jenkins³

et al. 2006

Mol Pharmacol

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Valproic acid (VPA) is an effective antiepileptic drug with an additional activity for the treatment of bipolar disorder. It has been assumed that both activities arise from a common target. At the molecular level, VPA targets a number of distinct proteins that are involved in signal transduction. VPA inhibition of inositol synthase reduces the cellular concentration of myo-inositol, an effect common to the mood stabilizers lithium and carbamazepine. VPA inhibition of histone deacetylases activates Wnt signaling via elevated ␤-catenin expression and causes teratogenicity. Given the VPA chemical structure, it may be possible to design VPA derivatives and analogs that modulate specific protein targets but leave the others unaffected. Indeed, it has been shown that some nonteratogenic VPA derivatives retain antiepileptic and inositol signaling effects. In this study, we describe a further set of VPA analogs and derivatives that separate anticonvulsant activity from effects on neuronal growth cone morphology. Lithium, carbamazepine, and VPA induce inositol-dependent spread of neuronal growth cones, providing a cell-based assay that correlates with mood-stabilizing activity. We find that two constitutional isomers of VPA, propylisopropylacetic acid and diisopropylacetic acid, but not their corresponding amides, and N-methyl-2,2,3,3-tetramethyl-cyclopropanecarboaxamide are more effective than VPA in increasing growth cone spreading. We show that these effects are associated with inositol depletion, and not changes in ␤-catenin-mediated Wnt signaling. These results suggest a route to a new generation of central nervous system-active VPA analogs that specifically target bipolar disorder.

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