Details

Autor(en) / Beteiligte

• Bello‐Ramírez, Angélica M.
• Carreón‐Garabito, Blanca Y.
• Nava‐Ocampo, Alejandro A.

Titel

Do Structural Properties Explain the Anticonvulsant Activity of Valproate Metabolites? A QSAR Analysis

Ist Teil von

• Epilepsia (Copenhagen), 2002-05, Vol.43 (5), p.475-481

Ort / Verlag

Boston, MA, USA: Blackwell Science Inc

Erscheinungsjahr

2002

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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 Poct (r2 = 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 Poct 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 Poct, probably reflecting the ability of VPA metabolites to cross the blood–brain barrier.