Characterization of the anticonvulsant profile of valpromide derivatives

Graphic The antiepileptic activity of nine derivatives of valpromide is discussed. They comply with a pharmacophore model that establishes the essential structural and electronic features responsible for the protection against the MES test. The model results from the comparison of 17 structures, usi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2004-07, Vol.12 (14), p.3857-3869
Main Authors: Tasso, Silvina M, Moon, Sung Ch, Bruno-Blanch, Luis E, Estiú, Guillermina L
Format: Article
Language:English
Subjects:
Animals
Anticonvulsant activity
Anticonvulsants - chemical synthesis
Anticonvulsants - chemistry
Anticonvulsants - pharmacology
Anticonvulsants. Antiepileptics. Antiparkinson agents
Antiepileptic drugs
Biological and medical sciences
Drug Evaluation, Preclinical
In Vitro Techniques
Magnetic Resonance Spectroscopy
Medical sciences
Mice
Mice, Inbred BALB C
Models, Molecular
Molecular Structure
Neuropharmacology
Pharmacology. Drug treatments
Pharmacophore
Structure-Activity Relationship
Valproic Acid - analogs & derivatives
Valproic Acid - chemical synthesis
Valproic Acid - chemistry
Valproic Acid - pharmacology
Valpromide derivatives
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Summary:Graphic The antiepileptic activity of nine derivatives of valpromide is discussed. They comply with a pharmacophore model that establishes the essential structural and electronic features responsible for the protection against the MES test. The model results from the comparison of 17 structures, using density functional methodologies combined with an active analog approach. The derivatives of valpromide have been tested for anticonvulsant activity in mice. These compounds displayed a phenytoin-like profile, being active in the MES test and inactive in the PTZ test. 4-(Valproylamido)benzenesulfonamide is the most active compound, with an ED 50 of 53 μmol/kg and no neurotoxicity at doses up to 1000 μmol/kg. The pharmacological behavior of the drugs points to a sodium channel blocking effect as one of the associated mechanisms. This mechanism was tested positive for N-ethylvalpromide through its competition with the binding of [ 3H]batrachotoxin-A-20α-benzoate to the voltage-dependent sodium channels from rat brain synaptosomes.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2004.05.003