RESUMO
The study examined the effect of 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α] benzimidazole dihydrochloride (RU-1205) on the latency of seizures provoked by corazol, bicuculline, or picrotoxin. This agent (10 and 20 mg/kg) increased the seizure latency in the experimental models of epileptogenesis. The blockers of GABAA and GABA A -ρ receptors picrotoxin and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid, respectively, were employed to study the effects of RU-1205 on electrical activity of somatosensory cortical neurons and on formation of pathological rhythms in the rat brain. RU-1205 inhibited the focal background rhythm and eliminated the epileptiform activity, which can be mediated by interaction with GABAA receptors.
Assuntos
Anticonvulsivantes/farmacologia , Benzimidazóis/farmacologia , Morfolinas/farmacologia , Receptores de GABA-A/metabolismo , Animais , Anticonvulsivantes/uso terapêutico , Benzimidazóis/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Camundongos , Morfolinas/uso terapêutico , Picrotoxina/farmacologia , RatosRESUMO
A putative opioid agonist RU-1205 was ineffective within in vitro model of electrically induced contractions of rat ileum assessing the µ- and δ-opioid receptor pathways, while morphine inhibited these contractions in a dose-dependent and naloxone-reversible manners with EC50=2.6×10-7 M. In vivo experiments revealed no significant effects of RU-1205 on respiration and gastrointestinal tract contractile activity. In contrast, butorphanol decreased respiration rate by 25% (25-100 mg/kg) and slowed down the transit of labeled particles along the small intestine by 77.1% (1 mg/kg) and by 45.5% (10 mg/kg). Morphine-induced inhibition of peristalsis was dose-dependent with maximum effect (by 68.6%) observed in the dose of 10 mg/kg. It was concluded that the effects of RU-1205 are not related to activation µ- and δ-opioid receptors known to mediate the effects of non-selective opioid agonist morphine and agonist-antagonist butorphanol.
Assuntos
Analgésicos Opioides/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/fisiologia , Animais , Benzimidazóis/farmacologia , Butorfanol/farmacologia , Avaliação Pré-Clínica de Medicamentos , Motilidade Gastrointestinal/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/fisiologia , Masculino , Morfina/farmacologia , Morfolinas/farmacologia , RatosRESUMO
Antiepileptic activity of a new derivative of benzimidazole RU-1205 was studied on the model of pentylenetetrazole-induced generalized seizures in mice. Sodium valproate was used as the reference substance. RU-1205 was superior to sodium valproate by anticonvulsant activity (by 12 times) and therapeutic index (by 8.5 times). In contrast to sodium valproate, RU-1205 exhibited significant anticonvulsant activity on the model of pentylenetetrazole-induced kindling without tendency to resistance development.
Assuntos
Anticonvulsivantes/uso terapêutico , Benzimidazóis/uso terapêutico , Morfolinas/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/química , Benzimidazóis/química , Excitação Neurológica/efeitos dos fármacos , Masculino , Camundongos , Morfolinas/química , Pentilenotetrazol/farmacologia , Convulsões/induzido quimicamente , Ácido Valproico/uso terapêuticoRESUMO
We have studied the physical dependence on and tolerance to the analgesic activity of compound RU-1205. It is established that this compound does not cause side effects typical of morphine and butorphanol including the development of withdrawal syndrome upon naloxone provocation and tolerance to analgesic activity upon 14-day administration.
Assuntos
Analgésicos/farmacologia , Benzimidazóis/farmacologia , Dependência de Morfina/prevenção & controle , Morfina/efeitos adversos , Morfolinas/farmacologia , Síndrome de Abstinência a Substâncias/prevenção & controle , Analgésicos Opioides/farmacologia , Animais , Animais não Endogâmicos , Butorfanol/farmacologia , Esquema de Medicação , Tolerância a Medicamentos , Masculino , Camundongos , Dependência de Morfina/metabolismo , Dependência de Morfina/fisiopatologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologiaRESUMO
The dose-dependent and reversible changes of sodium (I(Na)), calcium (I(ca)), slow potassium (I(Ks)), and fast potassium (I(Kf)) currents were recorded in isolated snail neurons under the action of κ-opioid agonist butorphanol and chemical agent RU-1203 applied in a concentration range of 1-1000 µM.
Assuntos
Butorfanol/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Neurônios/fisiologia , Receptores Opioides kappa/agonistas , Animais , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Potássio/metabolismo , Caramujos , Canais de Sódio/metabolismoRESUMO
RU-1203-induced norBNI-irreversible inhibition of sodium (INa), calcium (ICa), and slow and fast potassium currents (IKs and IKf) was demonstrated in isolated neurons of Lymnaea stagnalis.