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Quantitative structure-anticonvulsant activity studies of valproic acid analogues Acheampong, Andrew Adu


Valproic acid (2-propylpentanoic acid) is an antiepileptic drug widely used for treatment of absence seizures. Valproic acid has a unique chemical structure which does not contain the imide structure found in most conventional antiepileptic drugs. An in vivo study of the antagonism of pentylenetetrazol-induced clonic seizures by alkyl-substituted carboxylic acids and tetrazoles was of interest owing to the known bioisosterism between the carboxylic and the tetrazolyl moiety. The main objective of this study was to investigate the role played by the lipophilicity, the electronic properties and the steric influence of compounds on their anticonvulsant potency. Quantitative structure-activity relationships of the aliphatic and alicyclic substituted carboxylic acids and tetrazoles have been performed using the Hansch linear free-energy relationships model. The study proceeded by synthesis of compounds using known procedures. The di-unsaturated derivatives of valproic acid, 2-[(E)-l'-propenyl]-(E)-2-pentenoic acid and 2-[(Z)-l'-propenyl]-(E)-2-pentenoic acid were prepared via a stereoselective synthetic route. The synthesized di-unsaturated acids were used in identification of the major diunsaturated metabolite of valproic acid as 2-[(E)-l'-propenyl]-(E)-2-pentenoic acid. The anticonvulsant potency of test compounds was determined in mice (CD1 strain, 20-32g) by the standard subcutaneous pentylenetetrazole seizure threshold test. The pentylenetetrazole clonic seizure test was found to be more sensitive to structural effects than the pentylenetetrazole mortality assay. The lipophilicity (octanol-water partition coefficient) of compounds was determined indirectly by reversed phase liquid chromatography employing an octadecylsilane column (Hypersil ODS) and mobile phase as 70% methanol : 30% phosphate buffer (pH 3.5). The electronic character of the compounds was monitored by the apparent acid ionization constant obtained from potentiometric titration in 10% raethanol-water system. The ED₅₀ of 0.70 mmol/kg found for valproic acid was similar to literature values. 5-Heptyltetrazole was found to be the most potent compound in the series of analogues studied. The carboxylic plus tetrazole group gave a low correlation (r = 0.63) between the anticonvulsant potency and a linear combination of lipophilicity and apparent ionization constant. However, in the series of active carboxylic acids, the anticonvulsant activity was noted to be significantly correlated with lipophilicity and apparent ionization constant (r = 0.91). The usefulness of the electronic parameters, acid ionization constant and dipole moment, were explored in an extensive set of alkyl-substituted anticonvulsant compounds with different polar moieties. Addition of the dipole moment term to the lipophilicity term led to significantly better correlations (r = 0.81) as compared to that with an added pKa term. The negative dependency of anticonvulsant activity on dipole moment supported previous findings in studies of 1,4-benzo-diazepines and phenyl-substituted anticonvulsant compounds. There were some exceptions to the dependence of anticonvulsant activity on lipophilicity and dipole moment or pKa. N,N-dibutyl-succinamic acid showed convulsant properties at sublethal doses. The lack of activity of cyclohexylacetic acid and 5-cyclohexylmethyltetra-zole, in comparison to the active l-methylcyclohexanecarboxylic acid, has some pharmacological significance. It shows a certain degree of molecular specificity in the anticonvulsant action of valproic acid analogues. The cyclohexylmethyl conformation was suggested, from aproposed model, to be less effective in hydrophobic binding due to a steric effect at a stereoselective position on the hydrophobic site of the GABA receptor complex. Thus it can be concluded that while lipophilicity governed access to sites of action, the dependence of activity on the polar character may explain the diverse structures of anticonvulsants provided that the steric requirements of the hydrophobic binding site are met. Steric effects may lead to inactivity or even convulsant properties of alkyl-substituted compounds.

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