RESUMO
Research aimed at developing selective drugs acting on gamma-aminobutyric acid (GABA)A receptors introduced compounds from diverse chemical classes unrelated to the 1,4-benzodiazepines, including flavonoids. These studies also revealed the potential use of inverse agonists as cognition-enhancing agents. Here we report pharmacological properties of the novel synthetic isoflavonoid 2-methoxy-3,8,9-trihydroxy coumestan (PCALC36). PCALC36 displaced [3H]flunitrazepam binding to rat brain synaptosomes with an IC50 of 13.8 microM. Scatchard analysis of the effect of PCALC36 showed a concentration-dependent reduction of the Bmax of [3H]flunitrazepam, without a marked change in Kd. This effect could be reversed by diluting and washing the preparation. Addition of 20-microM GABA shifted to the right the inhibition curve of PCALC36 on [3H]flunitrazepam binding (IC50 ratio of 0.68), which is characteristic for inverse agonists. PCALC36 produced little change in the GABAergic tonic currents recorded by whole-cell patch clamp in cultured rat hippocampal neurones, but it caused a 20% reduction in miniature inhibitory postsynaptic current amplitude and completely antagonised the full (direct) agonist midazolam in a quickly reversible manner. The data suggest that the coumestan backbone can be useful for developing novel ligands at the GABAA receptor.
Assuntos
Flavonoides/farmacologia , Agonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , Isoflavonas/farmacologia , Análise de Variância , Animais , Bicuculina/farmacologia , Ligação Competitiva/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Flavonoides/síntese química , Flunitrazepam/metabolismo , Agonistas GABAérgicos/síntese química , Moduladores GABAérgicos/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Isoflavonas/síntese química , Isoflavonas/metabolismo , Cinética , Masculino , Potenciais da Membrana/efeitos dos fármacos , Midazolam/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Gravidez , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Sinaptossomos/metabolismo , Fatores de Tempo , Trítio , Ácido gama-Aminobutírico/farmacologiaRESUMO
Coumestans 2a-i, bearing different patterns of substitution in A- and D-rings, were synthesized and evaluated as inhibitors of kidney Na+, K+ -ATPase and ligands for the central benzodiazepine (BZP) receptor. The presence of a hydroxyl group in position 2 favours the effect on Na+, K+ -ATPase but decreases the affinity for the BZP receptor, allowing the design of more selective molecules than the natural wedelolactone. On the other hand, the presence of a catechol in ring D is important for the effect on both molecular targets.
Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Desenho de Fármacos , Receptores de GABA-A/metabolismo , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Catecóis/química , Catecóis/farmacologia , Cumarínicos/síntese química , Inibidores Enzimáticos/química , Humanos , Rim/enzimologia , Ligantes , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Seven new 1,4-naphthoquinones structurally related to lapachol were synthesized from lawsone and oxygenated arylmercurials. These compounds can also be seen as pterocarpan derivatives where the A-ring was substituted by the 1,4-naphthoquinone nucleus. Pharmacological screening provided evidence of significant biological activities, including effects against proliferation of the MCF-7 human breast cancer cell line, against Herpes Simplex Virus type 2 infection, and against snake poison-induced myotoxicity. One derivative displaced flunitrazepam binding and showed benzodiazepine-like activity, suggesting novel neuroactive structural motifs.