Synthalin sulfate

Interactions between zinc and spermidine on the N-methyl-D-aspartate receptor complex: clues to the mechanism of action of 1,10-bis(guanidino)decane and pentamidine.[Pubmed:1432693]

J Pharmacol Exp Ther. 1992 Nov;263(2):632-8.

This study investigated the mechanism of action of two novel, noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor using [3H]dizocilpine binding to rat brain membranes. Pentamidine and 1,10(bisguanidino)decane (BG10) inhibited [3H]dizocilpine binding in the concentration range of 1 to 100 microM, as did Zn++ and the competitive polyamine antagonist arcaine. The action of each of these agents was sensitive to the addition of spermidine to the assay. However, only arcaine interacted with spermidine in a competitive fashion. Spermidine decreased the apparent affinity of Zn++ and also increased the Hill slope of the Zn++ inhibition curves. BG10 and pentamidine inhibition of [3H]dizocilpine binding was less sensitive to spermidine. Calcium had similar effects to spermidine on the inhibition of [3H]dizocilpine binding by Zn++, arcaine, pentamidine and GB10, but was less potent than spermidine. Treating membranes with diethylpyrocarbonate, a histidine-modifying reagent, decreased the apparent affinity of Zn++ by more than 4-fold while having very modest effects on the actions of BG10, pentamidine and arcaine. In addition, Zn++ failed to slow the dissociation of [3H]dizocilpine in diethylpyrocarbonate-treated tissue, whereas the action of BG10 and pentamidine was qualitatively unaffected. These data show that the effects of BG10 and pentamidine on the NMDA receptor are complex and may involve more than one binding site for each drug. In addition, this study shows that the action of Zn++ on the NMDA receptor is modulated by polyamines. Finally, the mechanism of action of pentamidine and BG10 cannot be attributed to an action at the Zn++ recognition site.

1,10-bis(guanidino)decane inhibits N-methyl-D-aspartate responses in vitro and in vivo.[Pubmed:1658306]

J Pharmacol Exp Ther. 1991 Nov;259(2):626-32.

This study evaluated the interaction of the arcaine analog 1,10-bis(guanidino)decane (BG10) with the NMDA receptor. BG10 inhibited [3H]dizocilpine binding to well-washed rat brain membranes with an apparent affinity of 1.3 microM. The inhibition was not competitive with respect to glutamate or glycine, but was significantly altered by spermidine. However, unlike arcaine, BG10 slowed the dissociation of [3H]dizocilpine. BG10 also inhibited [3H]glycine binding at similar concentrations. BG10 inhibited N-methyl-D-aspartate (NMDA) and glycine-induced increases in intracellular Ca++ in cultured rat brain neurons monitored using the fluorescent dye, fura-2 (IC50 3 microM). This inhibition was not competitive with NMDA or glycine and could not be reversed by either spermidine or arcaine. BG10 also noncompetitively inhibited NMDA-stimulated cyclic GMP production in cerebellar slices from mouse brain. Finally, BG10 administered i.p. reduced harmaline-stimulated, NMDA-dependent cyclic GMP accumulation in mouse cerebellum in vivo (ED50 12.3 mg/kg). These data demonstrate that BG10 is a novel and effective NMDA receptor antagonist in vitro and in vivo.