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

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

doi:10.1016/j.neuropharm.2005.06.008

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it engages a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and are likely to be non-hepatotoxic, and that exhibit good antiepileptic efficacy. In the present study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. TMCA (2,2,3,3-tetramethylcyclopropanecarboxylic acid, 100-250 mg/kg), TMCD (2,2,3,3-tetramethylcyclopropanecarboxamide, 40-150 mg/kg), MTMCD (N-methyl-TMCD, 20-100 mg/kg), and TMCU (2,2,3,3- tetramethylcyclopropanecarbonylurea, 40-240 mg/kg) all showed dose-related reversal of tactile allodynia, with ED₅₀ values of 181, 85, 41, and 171 mg/kg i.p., respectively. All were more potent than VPA (ED₅₀ = 269 mg/kg). An antiallodynic effect was obtained for TMCD, MTMCD and TMCU at plasma concentrations as low as 23, 6 and 22 mg/L, respectively. MTMCD was found to be non-toxic, non-sedative and equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. Tetramethylcyclopropyl analogues of VPA amides have potential to become a new series of drugs for neuropathic pain treatment.

Original language	English
Pages (from-to)	1110-1120
Number of pages	11
Journal	Neuropharmacology
Volume	49
Issue number	8
DOIs	https://doi.org/10.1016/j.neuropharm.2005.06.008
State	Published - Dec 2005

Bibliographical note

Funding Information:
The paper is abstracted from the PhD thesis of Mr. Ilan Winkler in partial fulfillment of requirements for the PhD degree at The Hebrew University of Jerusalem. The authors wish to thank Mr. James Stables from the NIH-NINDS, USA for testing the compounds in the Anticonvulsant Screening Program and Ms. Pnina Raber and Anne Minert from the Institute of Life Sciences at The Hebrew University of Jerusalem for their skillful technical assistance. Supported by grants from the United States-Israel Binational Science Foundation (BSF) and The Horowitz Fund, Jerusalem, Israel.

Keywords

Neuropathic pain
Pharmacodynamics
Pharmacokinetics
Spinal nerve ligation
Tetramethylcyclopropylamide and its derivatives
Valproic acid analogues

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10.1016/j.neuropharm.2005.06.008

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title = "Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model of neuropathic pain",

abstract = "Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it engages a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and are likely to be non-hepatotoxic, and that exhibit good antiepileptic efficacy. In the present study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. TMCA (2,2,3,3-tetramethylcyclopropanecarboxylic acid, 100-250 mg/kg), TMCD (2,2,3,3-tetramethylcyclopropanecarboxamide, 40-150 mg/kg), MTMCD (N-methyl-TMCD, 20-100 mg/kg), and TMCU (2,2,3,3- tetramethylcyclopropanecarbonylurea, 40-240 mg/kg) all showed dose-related reversal of tactile allodynia, with ED50 values of 181, 85, 41, and 171 mg/kg i.p., respectively. All were more potent than VPA (ED50 = 269 mg/kg). An antiallodynic effect was obtained for TMCD, MTMCD and TMCU at plasma concentrations as low as 23, 6 and 22 mg/L, respectively. MTMCD was found to be non-toxic, non-sedative and equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. Tetramethylcyclopropyl analogues of VPA amides have potential to become a new series of drugs for neuropathic pain treatment.",

keywords = "Neuropathic pain, Pharmacodynamics, Pharmacokinetics, Spinal nerve ligation, Tetramethylcyclopropylamide and its derivatives, Valproic acid analogues",

author = "Ilan Winkler and Eyal Sobol and Boris Yagen and Amir Steinman and Marshall Devor and Meir Bialer",

note = "Funding Information: The paper is abstracted from the PhD thesis of Mr. Ilan Winkler in partial fulfillment of requirements for the PhD degree at The Hebrew University of Jerusalem. The authors wish to thank Mr. James Stables from the NIH-NINDS, USA for testing the compounds in the Anticonvulsant Screening Program and Ms. Pnina Raber and Anne Minert from the Institute of Life Sciences at The Hebrew University of Jerusalem for their skillful technical assistance. Supported by grants from the United States-Israel Binational Science Foundation (BSF) and The Horowitz Fund, Jerusalem, Israel.",

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AU - Steinman, Amir

AU - Devor, Marshall

AU - Bialer, Meir

N1 - Funding Information: The paper is abstracted from the PhD thesis of Mr. Ilan Winkler in partial fulfillment of requirements for the PhD degree at The Hebrew University of Jerusalem. The authors wish to thank Mr. James Stables from the NIH-NINDS, USA for testing the compounds in the Anticonvulsant Screening Program and Ms. Pnina Raber and Anne Minert from the Institute of Life Sciences at The Hebrew University of Jerusalem for their skillful technical assistance. Supported by grants from the United States-Israel Binational Science Foundation (BSF) and The Horowitz Fund, Jerusalem, Israel.

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

Abstract

Bibliographical note

Keywords

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