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Do structural properties explain the anticonvulsant activity of valproate metabolites? A QSAR analysis
Angélica M Bello-Ramírez1, Blanca Y Carreón-Garabito, Alejandro A Nava-Ocampo
1Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México. bello_ramirez_am@yahoo.com
Purpose:
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.