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.
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.
Reynolds
I J
IJ
University of Pittsburgh, Department of Pharmacology, Pennsylvania.
D000818:Animals; D001645:Biguanides / Q000378:metabolism; D001665:Binding Sites; D001923:Brain Chemistry; D004047:Diethyl Pyrocarbonate / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006146:Guanidines / Q000494:pharmacology*; D010419:Pentamidine / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013095:Spermidine / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
D001645:Biguanides; D006146:Guanidines; D016194:Receptors, N-Methyl-D-Aspartate; C005748:synthalin A; C006624:arcaine; D010419:Pentamidine; D016291:Dizocilpine Maleate; D015032:Zinc; D004047:Diethyl Pyrocarbonate; D013095:Spermidine