RESUMO
Tosyl-polyamine derivatives such as N-{4-[4-(guanidinobutylamino)-butylamino]butyl}-4-methylbenzenesulfonamide trihydrochroride (TsHSPMG) have been found to strongly inhibit macroscopic currents through heteromeric N-methyl-D-aspartate (NMDA) receptors (NR1/NR2A, NR1/NR2B) and Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (homomeric glutamate receptor 1) receptors expressed in Xenopus laevis oocytes on voltage-clamp recording. In the present study, it was found that the inhibition of NMDA receptor activity induced by tosyl-polyamine derivatives was voltage-dependent. Some mutations located in the intracellular region of the channel pore, such as NR1 E621Q and NR2B W607L, reduced the inhibition by tosyl-polyamine derivatives, suggesting that tosyl-polyamine derivatives penetrate deeply into the channel pore of NMDA receptors. The neuroprotective effects of tosyl-polyamine derivatives against cell injury caused by NMDA were investigated in cultured rat hippocampal neurons. Addition of 1 microM TsHSPMG to medium ablated the neurotoxicity induced by NMDA, and a similar effect was observed with 30 microM memantine. The neuroprotective effects of tosyl-polyamine derivatives on NMDA-induced seizures in mice were also assayed. Intracerebroventricular or intravenous injection of TsHSPMG (0.1 or 0.5 mg/kg) decreased the seizures induced by intraperitoneal injection of NMDA in mice. These findings indicate that tosyl-polyamine derivatives exhibit neuroprotective effects not only in primary cultured neurons but also in mice.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Fármacos Neuroprotetores/farmacologia , Poliaminas/farmacologia , Receptores de Glutamato/efeitos dos fármacos , Compostos de Tosil/farmacologia , Animais , Antraquinonas/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Clonagem Molecular , Compostos de Dansil/farmacologia , Eletrofisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Camundongos , N-Metilaspartato/antagonistas & inibidores , N-Metilaspartato/toxicidade , Neuroblastoma/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Oócitos/metabolismo , Técnicas de Patch-Clamp , Gravidez , Ratos , Receptores de AMPA/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Espermina/análogos & derivados , Espermina/farmacologia , Xenopus laevisRESUMO
Novel water-soluble N-methyl-D-aspartate (NMDA) receptor antagonists, 4,4'-bis([2-[N-(1,4,8,11-tetraazacyclotetradecan-1-yl)acetyl]-N-phenethyl]aminoethoxy)diphenylmethane octahydrochloride (1, ACPCm) and 4,4'-bis([2-[N-(1,4,7,10-tetraazacyclododecan-1-yl)acetyl]-N-phenethyl]aminoethoxy)diphenylmethane octahydrochloride (2, ACPCn), were synthesized and the effect of these cleft-type cyclophanes on NMDA receptors was then studied using voltage-clamp recordings of recombinant NMDA receptors expressed in Xenopus oocytes. ACPCm (1) and ACPCn (2) inhibited macroscopic currents in the NR1/NR2A, NR1/NR2B, NR1/NR2C and NR1/NR2D receptor subtypes in oocytes voltage-clamped at -70 mV. The IC50 values of ACPCm (1) and ACPCn (2) for NR1/NR2A and NR1/NR2B receptors were 1.06 microM and, 0.92 microM and 1.47 microM and, 1.49 microM, respectively. The inhibition by these compounds was voltage-dependent, that is, the degree of inhibition was in the order of negative holding potentials, -100 mV>-70 mV>-20 mV. These findings indicate that the cleft-type cyclophanes, ACPCm (1) and ACPCn (2) directly act on the channel pore of the NMDA receptors.