Pharmacological evaluation of various metabolites and analogues of valproic acid: Anticonvulsant and toxic potencies in mice

Abstract

Thirty-two metabolites and analogues of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) were tested for anticonvulsant and toxic effects in mice, in an attempt to find out if any of these compounds were superior to valproic acid. Valproic acid and ethosuximide, another clinically established antiepileptic drug, were included in these studies for comparison. After intraperitoneal administration, the anticonvulsant potency of the various drugs was determined in three Scizure tests: the threshold for maximal electroconvulsions, the maximal electroshock Scizure test and Scizures induced by subcutaneous injection of pentylenetetrazol. For the most potent compounds, median minimal neurotoxic doses (TD 50 s) and LD 50 s (after i.p. and i.v. injection) were determined. Valpramide, the primary amide of valproic acid, proved to be the most potent compound in the three Scizure tests, used, being 2–5 times as potent as valproic acid, but valpramide was also considerably more sedative and toxic than valproic acid or ethosuximide. Of the metabolites of valproic acid tested, the unsaturated compounds 4-en-valproic acid (4-en-VPA) and the trans-isomer of 2-en-valproic acid (2-en-VPA) were most potent and, depending on the Scizure test used, reached 60–100% of the efficacy of the parent drug. Both metabolites had LD 50, values which were similar or greater than those of valproic acid but they were more sedative than the parent compound. Analogues of valproic acid with shorter side-chain lengths were only weakly active as anticonvulsants, whereas elongation of the side-chains led to increases in anticonvulsant potency ut also in sedative/hypnotic side effects and toxicity, Non-branched monocarboxylic acids and cyclic compounds in which the side-chains have been closed to a ring were inactive or only weakly active. However, addition of a methyl group in position 1 at the ring of cyclohexanoic acid markedly increased the anticonvulsant potency without altering LD 50, values. Similarly, introduction of an additional branching with a methyl group at C2 of analogues of valproic acid led to considerable enhancement of anticonvulsant effectiveness. Although these methyl-substituted compounds were more sedative than valproic acid, they seem to be interesting tools with regard to the structural prerequisites of anticonvulsant, toxic and teratogenic effects of branched fatty acids.