RESUMO
Taurine activates and modulates GABA receptors in vivo as well as those expressed in heterologous systems. This study aimed to determine whether the structural analogs of taurine: homotaurine and hypotaurine, have the ability to activate GABA-A receptors that include GABAρ subunits. The expression of GABA-A receptors containing GABAρ has been reported in the STC-1 cells and astrocytes. In both cell types, taurine, homo-, and hypotaurine gated with low efficiency a picrotoxin-sensitive GABA-A receptor. The known bimodal modulatory effect of taurine on GABAρ receptors was not observed; however, differences between the activation and deactivation rates were detected when they were perfused together with GABA. In silico docking simulations suggested that taurine, hypo-, and homotaurine do not form a cation-π interaction such as that generated by GABA in the agonist-binding site of GABAρ. This observation complements the electrophysiological data suggesting that taurine and its analogs act as partial agonists of GABA-A receptors. All the observations above suggest that the structural analogs of taurine are partial agonists of GABA-A receptors that occupy the agonist-binding site, but their structures do not allow the proper interaction with the receptor to fully gate its Cl(-) channel.
Assuntos
Astrócitos/metabolismo , Receptores de GABA-A/química , Taurina/química , Animais , Astrócitos/citologia , Sítios de Ligação , Caenorhabditis elegans , Linhagem Celular , Simulação por Computador , Eletrofisiologia , Humanos , Cinética , Ligantes , Camundongos , Técnicas de Patch-Clamp , Perfusão , Picrotoxina/química , Ligação Proteica , Conformação Proteica , Taurina/análogos & derivadosRESUMO
The electrophysiological characterization of sesquiterpene lactones from Coriaria ruscifolia subsp. ruscifolia has been tested on hippocampal neurons. The results for glycinergic rat hippocampal transmission and native γ-aminobutyric acid (GABA)ergic transmission on neurons (13DIV) are remarkably different for tutin, coriamyrtin, and dihydrotutin, being tutin the most potent inhibitor and dihydrotutin the least potent one. To understand the applied mechanism of action, we discuss the structural and electronic requirements for inhibitory activity by these sesquiterpene lactones when modulating receptors of the central nervous system. The structural and electrostatic properties of these compounds were compared to those of more active metabolites like picrotoxins. The minimal energy level of these structures was calculated and then optimized at the ab initio B3LYP/DGDZVP level of theory using Gaussian 03W software. This allowed calculation of the corresponding vibrational circular dichroism spectrum of coriamyrtin which rendered the molecular absolute configuration after comparison with an experimental spectrum. These results are consistent with those from studies of other models that provide the basis for the activity on the presence of the lactone at carbons 3 and 5, the presence of the hydroxyl group at position 6, and the different electronic distributions observed in tutin and coriamyrtin. The latter has an isopropenyl moiety at carbon 4 in contrast to the dihydrotutin isopropyl group at the same position, which could explain the difference in activity between dihydrotutin and tutin or coriamyrtin. The presence of the hydroxyl group at carbon 2 is not decisive since this functionality is present in tutin, the most active compound, and in dihydrotutin, the less active one.
Assuntos
Biologia Computacional , Inibição Neural/efeitos dos fármacos , Picrotoxina/análogos & derivados , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiologia , Biologia Computacional/métodos , Lactonas/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Inibição Neural/fisiologia , Neurônios/química , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Picrotoxina/química , Picrotoxina/isolamento & purificação , Picrotoxina/farmacologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de GABA/fisiologia , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Difração de Raios XRESUMO
Se estudio la actividad farmacológica en animales de una serie nueva de compuestos anticonvulsionantes, la DL-4-hidroxil, 4-etil, 4-fenil butiramida (HEPB) y sus homólogos inferiores propionamida (HEPP) y acetamida (HEPA). La neurotoxidad fue determinada con un rotarod y se indujeron cuadros convulsivos con electrochoque supramáximo (MES), pentilentetrazol (TSC), estricnina (STR) y picrotoxina (PIC). HEPP es menos neurotóxica que HEPB y HEPA y altera el comportamiento de los ratones solamente a dosis altas. Los tres compuestos presentaron un amplio espectro de acción anticonvulsionante. Ellos son muy potentes para inhibir cuadros convulsivos inducidos con 4-AP, BIC, TSC y PTZ en dosis no tóxicas administradas ip, pero son inefectivas contra convulsiones inducidas con pic y STR. Los índices terapéuticos (IT = DT 50/D 50) fueron más elevados para HEPP. En consecuencia los resultados indican que los tres compuestos probados pueden servir para el tratamiento de convulsiones generalizadas tipo ausencias. Puesto que HEPP es el compuesto menos neurotóxico se ha seleccionado para los estudios toxicológicos y neuroquímicos