RESUMO
κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.
Assuntos
Analgésicos/farmacologia , Descoberta de Drogas , Morfinanos/farmacologia , Dor/tratamento farmacológico , Receptores Opioides kappa/agonistas , Compostos de Espiro/farmacologia , Ácido Acético , Analgésicos/síntese química , Analgésicos/química , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Conformação Molecular , Morfinanos/síntese química , Morfinanos/química , Dor/induzido quimicamente , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor are attractive targets in the development of drugs for pain and pruritus. We previously reported the synthesis of 10α-hydroxy TRK-820 (1). In this study, we elucidated the biological properties of 1 and optimized its 6-acyl unit by modifying our synthetic route. Among the 10α-hydroxy TRK-820 derivatives prepared, 26 showed the most potent κ-opioid agonist activity (EC50=0.00466nM) and excellent selectivity and 22 was the most κ-selective agonist.
Assuntos
Analgésicos/farmacologia , Descoberta de Drogas , Morfinanos/farmacologia , Neuralgia/tratamento farmacológico , Receptores Opioides kappa/agonistas , Compostos de Espiro/farmacologia , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Morfinanos/administração & dosagem , Morfinanos/química , Ratos , Compostos de Espiro/administração & dosagem , Compostos de Espiro/química , Relação Estrutura-Atividade , Substância P/administração & dosagem , Substância P/farmacologiaRESUMO
Nalfurafine hydrochloride [(E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6ß-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; nalfurafine] is used in Japan as an antipruritic for the treatment of intractable pruritus in patients undergoing hemodialysis or with chronic liver disease. It is a potent and selective agonist at the κ opioid receptor, but also has weak and partial agonist activity at µ opioid receptors. Opioids, especially those acting at µ receptors, carry a risk of abuse. This is an important factor in the consideration of therapeutic risk vs. benefit in clinical use and the potential for misuse as a public health problem. It is therefore necessary to carefully evaluate the reinforcing effects of nalfurafine. To this end, we investigated intravenous self-administration of nalfurafine in rhesus monkeys. The number of self-administration of nalfurafine at doses of 0.0625, 0.125 and 0.25 µg/kg/infusion was not higher than that of saline in rhesus monkeys that frequently self-administered pentazocine (0.25 mg/kg/infusion). These results indicate that nalfurafine has no reinforcing effect in rhesus monkeys in the intravenous self-administration paradigm.
