RESUMO
Following our studies of the melatoninergic receptors, we have developed new tetrahydronaphthalenic derivatives of melatonin that have been tested as selective melatonin receptors ligands. Regarding the role of the phenyl substituent to obtain selective ligands, modulation of selectivity and activity have been achieved by modifications of the acyl group and substitutions on the phenyl ring. Ten of the seventeen evaluated derivatives have MT(2) receptor affinity similar to that of melatonin. Moreover, we have achieved remarkable MT(2) selectivity over MT(1) (selectivity >100) and have been able to further extend the RSA of the tetrahydrophthalenic series. However, the compounds presented here display partial agonist or antagonist behavior instead of full agonist.
Assuntos
Melatonina/análogos & derivados , Receptor MT2 de Melatonina/metabolismo , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologia , Animais , Células CHO , Técnicas de Cultura de Células , Linhagem Celular , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ligantes , Melatonina/metabolismo , Receptor MT2 de Melatonina/química , Relação Estrutura-Atividade , Especificidade por Substrato , TransfecçãoRESUMO
[structure: see text]. The first enantioselective total synthesis of 1-epi-pathylactone A, 3, has been accomplished using a PhI(OAc)2-mediated domino reaction as a key step. No diastereomeric separation was required throughout the whole synthetic scheme presented in this paper. Comparison of 1H and 13C NMR spectral data of the synthetic product with the reported spectral data of natural pathylactone A, coupled with an X-ray crystallographic analysis, led to the conclusion that the C1 configuration in the original paper was erroneously ascribed to (R).