RESUMO
In our screening program for new biologically active secondary metabolites, nine new polycyclic polyprenyled acylphloroglucinols, hyperscabins D-L, together with three known compounds, were obtained from the aerial parts of Hypericum scabrum. The chemical structures of 1-9 were characterized by extensive spectroscopic analyses, nuclear magnetic resonance calculation with DP4+ probability analysis, and the electronic circular dichroism spectra were calculated. Compound 1 was an unusual prenylated acylphloroglucinol decorated with a 5-oxaspiro [4,5] deca-1,9-dione skeleton. Compound 2 was a newly identified spirocyclic polyprenylated acylphloroglucinol possessing a rare 5,5-spiroketal segment. Compounds 3, 8, and 10 (10 µM) exhibited pronounced hepatoprotective activity against d-galactosamine-induced WB-F344 cell damage in vitro assays. All test compounds (1, 3, and 7-12) demonstrated potential inhibitory effects at 10 µM against noradrenalinet ([3H]-NE) reuptake in rat brain synaptosome.
Assuntos
Antidepressivos/farmacologia , Hemiterpenos/farmacologia , Hypericum/química , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Substâncias Protetoras/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/isolamento & purificação , Linhagem Celular , Hemiterpenos/síntese química , Hemiterpenos/isolamento & purificação , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/isolamento & purificação , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Floroglucinol/isolamento & purificação , Componentes Aéreos da Planta/química , Substâncias Protetoras/síntese química , Substâncias Protetoras/isolamento & purificação , Ratos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
We demonstrate that the phloroglucinol derivative hyperforin is not only the major lipophilic chemical constituent of the medicinal plant Hypericum perforatum (St. John's wort) but also a potent uptake inhibitor of serotonin (5-HT), dopamine (DA), noradrenaline (NA), GABA and L-Glutamate with IC50 values of about 0.05-0.10 microg/ml (5-HT, NA, DA, GABA) and about 0.5 microg/ml (L-glutamate) in synaptosomal preparations. Furthermore, potencies of two different hypericum extracts in two conventional pharmacological paradigms useful for the detection of antidepressants (behavioral despair, learned helplessness), closely correlate with their hyperforin contents. In addition, most till now known neuropharmacological properties of the clinically used hypericum extracts can also be demonstrated with pure hyperforin. It appears, therefore, that this non-nitrogenous constituent is a possible major active principle responsible for the observed clinical efficacies of the extract as an antidepressant and that it could also be a starting point for drug discovery projects engaged in the search of psychoactive drugs with novel mode of action.