RESUMO
We previously identified a pyridomorphinan (6, SRI-22138) possessing a 4-chlorophenyl substituent at the 5'-position on the pyridine and a 3-phenylpropoxy at the 14-position of the morphinan as a mixed µ opioid receptor (MOR) agonist and δ/κ opioid receptor (DOR/KOR) antagonist with potent antinociceptive activity and diminished tolerance and dependence in rodents. Structural variations at the 5'- and 14-positions of this molecule gave insights into the structure-activity relationships for binding and functional activity. Subtle structural changes exerted significant influence, particularly on the ability of the compounds to function as agonists at the MOR. In vivo evaluation identified compound 20 (SRI-39067) as a MOR agonist/DOR antagonist that produced systemically active potent antinociceptive activity in tail-flick assay in mice, with diminished tolerance, dependence/withdrawal, reward liability, and respiratory depression versus morphine. These results support the hypothesis that mixed MOR agonist/DOR antagonist ligands may emerge as novel opioid analgesics with reduced side effects.
Assuntos
Analgésicos Opioides/uso terapêutico , Morfinanos/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Piridinas/uso terapêutico , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/agonistas , Analgésicos Opioides/síntese química , Analgésicos Opioides/metabolismo , Animais , Células CHO , Cricetulus , Desenho de Fármacos , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfinanos/síntese química , Morfinanos/metabolismo , Antagonistas de Entorpecentes/síntese química , Antagonistas de Entorpecentes/metabolismo , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-AtividadeRESUMO
An intramolecular Diels-Alder reaction of a silyl-substituted vinylimidazole delivers a diastereomeric mixture of C4-silyl functionalized dihydrobenzimidazoles. Subsequent diastereoselective reduction and elaboration of the lactone gives rise to a polysubstituted tetrahydrobenzimidazole, which, upon oxidative rearrangement, affords a single spirofused imidazolone containing all of the relevant functionality for an approach to the oroidin dimers axinellamine, massadine, and palau'amine.
RESUMO
A Diels-Alder/rearrangement sequence has been pursued in our lab en route to a number of oroidin dimers. In order to access the fully substituted core of these molecules, 1',2'-disubstituted 4-vinylimidazoles were required as dienes. The preparation of a series of a 4-vinylimidazoles containing substituents on the vinyl moiety via hydroalumination/electrophilic trapping or hydrosilylation are described. These derivatives undergo Diels-Alder reactions with N-phenylmaleimide to provide the tetrahydrobenzimidazole derivatives. The cycloadducts derived from halosubstituted systems generally undergo elimination, leading to the corresponding dihydrobenzimidazole, whereas the silyl and stannyl derivatives provide the corresponding 4-substituted tetrahydrobenzimidazole.