A spirohydantoin derivative of oxymorphone: an agonist with delayed antagonist activity.

We have synthesized a novel derivative of oxymorphone, oxymorphone-6 alpha-spirohydantoin. The derivative was less toxic in mice than the parent compound and it showed a significant anticonvulsive activity. It exerted agonist effects in doses lower than those of morphine and its agonist effects were longer lasting. Furthermore, both oxymorphone and the 6-spirohydantoin showed definite antagonist properties 48 hr later: they prevented analgesic effects of morphine. The antagonist effects of the derivative persisted for a week.

Prevention of hyperthermia-induced seizures in immature rats by a hydantoin derivative of naloxone.

The non-specific opiate antagonist naloxone protects immature rats from hyperthermic seizures which occur when the animals are exposed to an environment of 40 degrees C and 55% humidity. Most of the currently used antiepileptic therapeutic agents can be said to contain either a hydantoin or a moiety stereochemically closely related to one. We have added a hydantoin group to naloxone and created a new combined chemical, naloxyl-6-alpha spirohydantoin. The new compound was ten times as effective as naloxone against hyperthermic seizures in 15-day old rat pups. Unlike naloxone, the new naloxone-hydantoin derivative retained a protective effect 24 hrs after injection.

Eboracin: a substituted indenopyrrole active against metrazol-induced, audiogenic and electroshock seizures in mice.

1. Pretreatment with eboracin, a methyl ester of a trioxyindenopyrrole, inhibited the tonic phase of pentylenetetrazol (Metrazol)-induced, audiogenic and electroshock seizures in mice. 2. In animals challenged with Metrazol a dose of 28 mg/kg eboracin prevented 50% of tonic-clonic responses. 3. In animals exposed to electroshock or auditory stimulation the dose required to produce a 50% reduction in tonic-clonic seizures was 30 mg/kg and 35 mg/kg, respectively. 4. The 50% lethal dose was 832 mg/kg, indicative of eboracin's relatively low toxicity and high therapeutic index. 5. Pretreatment with eboracin led to a prolongation of the myoclonic phase of Metrazol seizures, similar to that observed after phenytoin.

Onset of audiogenic seizures in rodents after intake of near-toxic doses of rubidium chloride.

Rats and mice that were not genetically or otherwise predisposed toward audiogenic seizures were rendered susceptible to auditory stimuli by chronic treatment with large doses of rubidium chloride (RbCl). Animals given drinking water, 0.03 N with respect to RbCl, for four weeks responded with convulsive seizures when exposed to signals of 2 to 22 kHz and 74 dbA. The rate of development of audiosusceptibility was dose-related. Less rubidium was needed if the diet was deficient in potassium. No differences were found between tissue rubidium in treated rats which became audiosensitive and their counterparts which remained resistant to auditory stimuli.