RESUMO
New N-heteroarylcarbonylalanines of the D-series were stereoselectively prepared from enoates derived from D-mannitol. These compounds were active in binding and functional assays of the NMDA sub-type of glutamate receptors. A pyridine derivative inhibited MK801 binding, protected neurons from excitotoxic damage and blocked NMDA-induced currents in neurons. A thiophene derivative positively modulated the NMDA receptor, possibly through the allosteric glycine site.
Assuntos
Alanina/síntese química , Alanina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Córtex Cerebral/metabolismo , Maleato de Dizocilpina/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Ligantes , Ligação Proteica/fisiologia , Ratos , Ratos Wistar , Estereoisomerismo , Tiofenos/síntese química , Tiofenos/metabolismoRESUMO
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
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.
