RESUMO
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
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
Pharmacokinetics of morpholinoethylimidazobenzimidazole derivative RU-1205 with kappa-agonist activity have been studied. The pharmacokinetic parameters were determined upon intravenous (10 mg/kg), peroral, and subcutaneous (50 mg/kg) administration. It is established that RU-1205 substance has high bioavailability (44.17 and 56.03% upon peroral and subcutaneous introduction, respectively).
Assuntos
Benzimidazóis/farmacologia , Benzimidazóis/farmacocinética , Morfolinas/farmacologia , Morfolinas/farmacocinética , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Masculino , RatosRESUMO
The pharmacokinetic properties of a new imidazobenzimidazole derivative, compound RU-1205, were studied after peroral administration to rabbits at a dose of 50 mg/kg as a parent substance and in coated tablet dosage form. It was found that RU-1205 tablets are characterized by high values of the relative bioavailability (105.3 +/- 11.7%). The results of hot-plate and vinegar-cramp tests showed that both the dosage form and parent substance produced the same analgesic effect. Granulated RU-1205 produced maximum analgesic effect (138.8% relative to control) within 4-h investigation and retained higher analgesic activity compared to that of parent substance (on the average by 58%, p < 0.05) up to 12 h.