title: Characterization of the anticonvulsant profile of valpromide derivatives.
abstract: 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 micromol/kg and no neurotoxicity at doses up to 1000 micromol/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 [(3)H]batrachotoxin-A-20 alpha-benzoate to the voltage-dependent sodium channels from rat brain synaptosomes.
authors.affiliation: Medicinal Chemistry, Department of Biological Sciences, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, B1900AVV La Plata, Argentina.
authors.forename: Silvina M
authors.initials: SM
authors.lastname: Tasso
authors.forename: Sung Ch
authors.initials: SCh
authors.lastname: Moon
authors.forename: Luis E
authors.initials: LE
authors.lastname: Bruno-Blanch
authors.forename: Guillermina L
authors.initials: GL
authors.lastname: Estiú
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid; C004651:dipropylacetamide