RESUMO
µ opioid receptor (MOR) agonists have been widely applied for treating moderate to severe pain. However, numerous adverse effects have been associated with their application, including opioid-induced constipation (OIC), respiratory depression, and addiction. On the basis of previous work in our laboratory, NAP, a 6ß- N-4'-pyridyl substituted naltrexamine derivative, was identified as a peripheral MOR antagonist that may be used to treat OIC. To further explore its structure-activity relationship, a new series of NAP derivatives were designed, synthesized, and biologically evaluated. Among these derivatives, NFP and NYP significantly antagonized the antinociception effect of morphine. Whereas NAP acted mainly peripherally, its derivatives NFP and NYP actually can act centrally. Furthermore, NFP produced significantly lesser withdrawal symptoms than naloxone at similar doses. These results suggest that NFP has the potential to be a lead compound to treat opioid abuse and addiction.
Assuntos
Desenho de Fármacos , Morfinanos/química , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Analgésicos Opioides/farmacologia , Animais , Sítios de Ligação , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Ligantes , Masculino , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Morfinanos/metabolismo , Morfinanos/uso terapêutico , Morfina/farmacologia , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Relação Estrutura-AtividadeRESUMO
Two representative spirostanol saponins that have the typical structure for the sugar moiety, diosgenyl alpha-L-rhamnopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->3)]-beta-D-glucopyranoside (gracillin) and diosgenyl alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->4)]-beta-D-glucopyranoside (dioscin), were easily synthesized by a general approach. A procedure using guanidine for the selective deblocking of acetyl while retaining benzoyl protecting groups is described.