title: Do structural properties explain the anticonvulsant activity of valproate metabolites? A QSAR analysis.
abstract: OBJECTIVE
  Differences in potency among valproate (VPA) metabolites could be explained by structural properties. Therefore, a quantitative structure-activity relation (QSAR) analysis was performed to study the relation between structural parameters and the effect of the following VPA metabolites: 4-en-VPA, 2-en-VPA, 3-en-VPA, 2,4'-dien-VPA, 4,4'-dien-VPA, 4-hydroxy-VPA, 3-ceto-VPA, 3-hydroxy-VPA, 5-hydroxy-VPA, and propylglutaric acid.
  
  
  METHODS
  By using the CAChe program package for biomolecules (Oxford Molecular, Ltd), we performed molecular modeling. The anticonvulsant activity determined on the threshold for maximal electroconvulsions in mice was obtained from a study of Löscher and Nau. Structural parameters were compared between metabolites with a double bond and metabolites with oxygen at either side chain (unpaired Student's t test). A single linear regression analysis between each structural parameter and the relative anticonvulsant potency was also performed.
  
  
  RESULTS
  Similar parameters were found between the cis and trans and R and S isomers. Biologic activity and most of the structural parameters were significantly different between metabolites with a double bond and metabolites with oxygen at either side chain. Activity was directly related to log P(oct) (r(2) = 0.77) and to reactivity parameters and was inversely related to stability parameters and to molecular weight and surface. The most potent metabolites had a log P(oct) value of higher than 2 units.
  
  
  CONCLUSIONS
  Similar data were identified between cis and trans, and R and S isomers of VPA metabolites. Anticonvulsant activity was mainly related to log P(oct), probably reflecting the ability of VPA metabolites to cross the blood-brain barrier.
authors.affiliation: Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México. bello_ramirez_am@yahoo.com
authors.forename: Angélica M
authors.initials: AM
authors.lastname: Bello-Ramírez
authors.forename: Blanca Y
authors.initials: BY
authors.lastname: Carreón-Garabito
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Nava-Ocampo
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D004827:Epilepsy / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008297:Male; D051379:Mice; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D014635:Valproic Acid / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid