Anticonvulsant properties of spirohydantoins derived from optical isomers of camphor

Abstract

Natural camphor exists as thed(+) form but thel(−) form has been synthesized. Replacement of the keto group on carbon 2 of each form with a hydantoin moiety led to only one spirohydantoin derivative. Bothd andl derivatives were synthesized. Both forms and their racemic mixture were tested in vivo for toxicity and behavioral effects in mice. A dose of 100 mg/kg of thed form was not toxic: mice showed normal grooming and exploratory behavior; thel form induced hunched posture, body jerks and myoclonic manifestations followed by quiescence. Thedl form showed intermediate effects. Challenge with the convulsant pentylenetetrazol (Metrazol) 2 hr after treatment with placebo or the camphor spirohydantoins produced seizure manifestations in all controls, in half of the subjects pretreated with thed-camphor derivative, in none of those pretreated with thel derivative and an intermediate response in those pretreated with racemic mixture. Thus, a spirohydantoin moiety added to camphor conferred strong anticonvulsive properties on thel form and modest ones on thed form; thed form did not seem to antagonize thel form.