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Do Structural Properties Explain the Anticonvulsant Activity of Valproate Metabolites? A QSAR Analysis
Author(s) -
BelloRamírez Angélica M.,
CarreónGarabito Blanca Y.,
NavaOcampo Alejandro A.
Publication year - 2002
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1046/j.1528-1157.2002.365011.x
Subject(s) - chemistry , anticonvulsant , quantitative structure–activity relationship , metabolite , potency , stereochemistry , pharmacology , biochemistry , epilepsy , in vitro , biology , neuroscience
Summary: 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.