Inorganic iron complexes derived from the nitric oxide donor nitroprusside: competitive N-methyl-D-aspartate receptor antagonists with nanomolar affinity.
Aquopentacyanoferrate(II), [Fe(II)H2O(CN)5]3-, is one of the photodegradation products of the vasodilator and nitric oxide donor nitroprusside. Earlier observations concerning the light dependence of N-methyl-D-aspartate (NMDA) receptor blockade by nitroprusside prompted us to examine the effects of this iron complex on the NMDA receptor. [Fe(II)H2O(CN)5]3- and two other related species, aminopentacyanoferrate(II) and aminopentacyanoferrate(III), were found to be highly potent, competitive, and selective NMDA receptor antagonists. In a binding assay for the transmitter recognition site on the NMDA receptor, these iron complexes displaced the radioligand [3H]CGP 39653 with nanomolar affinities. They did not displace radioligands labeling the channel ([3H]MK-801) or the glycine co-agonist ([3H]glycine) sites of the NMDA receptor, nor did they have any relevant affinities for a number of other neurotransmitter (alpha-adrenergic, 5-hydroxytryptamine, dopamine, opiate) receptors. The iron complexes blocked NMDA-induced depolarizations in rat cortical slices at submicromolar concentrations, whereas responses to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate were not affected. In another functional receptor assay (potentiation of [3H]MK-801 binding by glutamate under non-equilibrium conditions), Schild analysis demonstrated the competitive nature of the NMDA receptor antagonism. The pA2 values obtained from these experiments were similar to the pK(i) values derived from radioligand ([3H]CGP 39653) binding assays. To explain the high affinity and selectivity of these compounds for the NMDA receptor, a novel mechanism of antagonist-receptor interaction is proposed, involving a ligand exchange process in which a loosely bound species (here H2O or NH3) in the coordination sphere of the iron complex is replaced by a functional group of an amino acid side chain placed at the glutamate recognition site of the NMDA receptor, thereby hindering agonist binding.
Neijt
H
H
Novartis Pharma AG, Therapeutic Area Nervous System, CH-4002, Basel, Switzerland.
Koller
M
M
Urwyler
S
S
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005295:Ferrocyanides / Q000494:pharmacology; D066298:In Vitro Techniques; D058085:Iron Compounds / Q000737:chemistry / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000737:chemistry*; D009599:Nitroprusside / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014316:Tritium
D018691:Excitatory Amino Acid Antagonists; D005295:Ferrocyanides; D058085:Iron Compounds; D020030:Nitric Oxide Donors; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; C069052:CGP 39653; C020704:aquapentacyanoferrate; D009599:Nitroprusside; D015763:2-Amino-5-phosphonovalerate