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
Pharmacokinetic properties of imidazobenzimidazole derivative compound RU-1205 were investigated after subcutaneous administration to rabbits as a substance and a dosage form (lyophilisates for injection) at a dose of 25 mg/kg. The lyophilisate was characterized by high values of the relative bioavailability. In tests, the "hot plate" and "vinegar cramps" the dosage form and the substance exhibited the same analgesic effect.
Assuntos
Analgésicos/farmacologia , Benzimidazóis/farmacologia , Morfolinas/farmacologia , Cãibra Muscular/prevenção & controle , Dor/prevenção & controle , Ácido Acético , Analgésicos/sangue , Analgésicos/farmacocinética , Animais , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Liofilização , Injeções Subcutâneas , Camundongos , Morfolinas/sangue , Morfolinas/farmacocinética , Cãibra Muscular/induzido quimicamente , Cãibra Muscular/metabolismo , Cãibra Muscular/fisiopatologia , Dor/induzido quimicamente , Dor/metabolismo , Dor/fisiopatologia , Coelhos , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismoRESUMO
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.
Assuntos
Analgésicos não Narcóticos/farmacocinética , Benzimidazóis/farmacocinética , Morfolinas/farmacocinética , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Masculino , Morfolinas/química , Morfolinas/farmacologia , Coelhos , ComprimidosRESUMO
It is eastablished that kappa-opioid receptors have complicated structure. These receptors may play the important role in different processes in CNS.
Assuntos
Encéfalo/metabolismo , Dor/metabolismo , Receptores Opioides kappa/química , Medula Espinal/metabolismo , Sequência de Aminoácidos , Analgésicos Opioides/síntese química , Analgésicos Opioides/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Regulação da Expressão Gênica , Humanos , Dados de Sequência Molecular , Dor/tratamento farmacológico , Dor/fisiopatologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologiaRESUMO
We have studied the analgesic activity of a morpholinoethylimidazobenzimidazole derivative (RU-1205) in comparison to butorphanol. It is established that the test compound exhibits a pronounced analgesic activity, which exceeded that ofbutorphanol six times in the hot-plate test and was comparable to the reference drug effect in the tail-flick and acetic acid-induced writhing tests. It is established that the analgesic action of RU-1205 is based on the kappa-opioidergic mechanism.
