Inorganic iron complexes derived from the nitric oxide donor nitroprusside: competitive N-methyl-D-aspartate receptor antagonists with nanomolar affinity

Aquopentacyanoferrate(II), [(FeH2O)-H-II(CN)(5)](3-), is one of the photode gradation products of the vasodilator and nitric oxide donor nitroprusside. Earlier observations concerning the light dependence of N-methyl-D-asparta te (NMDA) receptor blockade by nitroprusside prompted us to examine the eff ects of this iron complex on the NMDA receptor. [(FeH2O)-H-II(CN)(5)](3-) a nd two other related species, aminopentacyanoferrate(II) and aminopentacyan oferrate(III), were found to be highly potent, competitive, and selective N MDA receptor antagonists. In a binding assay for the transmitter recognitio n site on the NMDA receptor, these iron complexes displaced the radioligand [H-3]CGP 39653 with nanomolar affinities. They did not displace radioligan ds labeling the channel ([H-3]MK-801) or the glycine co-agonist ([H-3]glyci ne) sites of the NMDA receptor, nor did they have any relevant affinities f or a number of other neurotransmitter (alpha -adrenergic, 5-hydroxytryptami ne, dopamine, opiate) receptors. The iron complexes blocked NMDA-induced de polarizations in rat cortical slices at submicromolar concentrations. where as responses to alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( AMPA) and kainate were not affected. In another functional receptor assay ( potentiation of [H-3]MK-801 binding by glutamate under non-equilibrium cond itions), Schild analysis demonstrated the competitive nature of the NMDA re ceptor antagonism. The pA(2) values obtained from these experiments were si milar to the pK(i) values derived from radioligand ([H-3]CGP 39653) binding assays. To explain the high affinity and selectivity of these compounds fo r the NMDA receptor, a novel mechanism of antagonist-receptor interaction i s proposed, involving a ligand exchange process in which a loosely bound sp ecies there H2O or NH3) in the coordination sphere of the iron complex is r eplaced by a functional group of an amino acid side chain placed at the glu tamate recognition site of the NMDA receptor, thereby hindering agonist bin ding. (C) 2001 Elsevier Science Inc. All rights reserved.