RESUMO
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.
Assuntos
Analgesia , Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Hidantoínas/farmacologia , Hidromorfona/análogos & derivados , Morfina/antagonistas & inibidores , Oximorfona/análogos & derivados , Dor/fisiopatologia , Animais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Avaliação Pré-Clínica de Medicamentos , Hidantoínas/síntese química , Masculino , Camundongos , Morfina/farmacologia , Oximorfona/síntese química , Oximorfona/farmacologia , Limiar Sensorial/efeitos dos fármacos , Fatores de TempoRESUMO
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.
Assuntos
Hidantoínas/farmacologia , Hipertermia Induzida , Naloxona/farmacologia , Convulsões/prevenção & controle , Animais , Temperatura Corporal , Ambiente Controlado , Febre/mortalidade , Febre/prevenção & controle , Naloxona/análogos & derivados , Ratos , Ratos Endogâmicos , Convulsões/mortalidade , Cloreto de SódioAssuntos
Anticonvulsivantes/uso terapêutico , Indenos/uso terapêutico , Ninidrina/uso terapêutico , Convulsões/tratamento farmacológico , Ureia/análogos & derivados , Animais , Anticonvulsivantes/síntese química , Fenômenos Químicos , Química , Avaliação Pré-Clínica de Medicamentos , Camundongos , Ninidrina/análogos & derivados , Uracila/análogos & derivados , Uracila/uso terapêutico , Ureia/uso terapêuticoRESUMO
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.