STRUCTURE-ACTIVITY-RELATIONSHIPS OF UNSATURATED ANALOGS OF VALPROIC ACID

The principal metabolite of valproic acid (VPA), 2-ene VPA, appears to share most of VPA's pharmacological and therapeutic properties while lacking its hepatotoxicity and teratogenicity, thus making it a useful lead compound for the development of safer antiepileptic drugs. Analo gues of 2-ene VPA were evaluated for anticonvulsant activity in mice u sing the subcutaneous pentylenetetrazole test. Cyclooctylideneacetic a cid exhibited a potency markedly exceeding that of VPA itself with onl y modest levels of sedation. Potency, as either ED(50) or brain concen tration, was highly correlated (r > 0.85) with volume and lipophilicit y rather than with one of the shape parameters calculated by molecular modeling techniques, arguing against the existence of a specific rece ptor site. Instead, a role for the plasma membrane in mediating the an ticonvulsant effect is suggested.