FURTHER BRANCHING OF VALPROATE-RELATED CARBOXYLIC-ACIDS REDUCES THE TERATOGENIC ACTIVITY, BUT NOT THE ANTICONVULSANT EFFECT

In the present study, compounds derived from the anticonvulsant drug v alproic acid (VPA, 2-n-propylpentanoic acid) and analogues known to be teratogenic were synthesized with an additional carbon-branching in o ne of the side chains. The substances were tested for their ability to induce anticonvulsant-activity and sedation in adult mice, and neural tube defects (exencephaly) in the offspring of pregnant animals (Han: NMRI mice). In all cases, the rates of exencephaly, embryolethality, a nd fetal weight retardation induced by the methyl-branched derivatives were very low when compared to those of the parent compounds, These n ovel compounds exhibited anticonvulsant activity which was not signifi cantly different from that of VPA. Neurotoxicity was considerably lowe r for some compounds as compared to VPA. Anticonvulsant activity and n eurotoxicity of branched short chain fatty acids are far less structur e-dependent and not related to teratogenic potency. Within this series of compounds, (+/-)-4-methyl-2-n-propyl-4-pentenoic acid and (+/-)-2- isobutyl-4-pentenoic acid exhibited the most favorable profile in rega rd to high anticonvulsant effect, low sedation, and teratogenicity. Va lproic acid analogues with additional methyl branching may be valuable antiepileptic agents with low teratogenic potential.