Radioligand binding studies reveal agmatine is a more selective antagonist for a polyamine-site on the NMDA receptor than arcaine or ifenprodil

• Published in: Brain research Vol. 952; no. 1; pp. 71 - 77
• Main Authors: Gibson, D.Alex, Harris, Barton R, Rogers, D.Trent, Littleton, John M
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 11.10.2002; Amsterdam Elsevier; New York, NY
• Subjects: Agmatine; Agmatine - metabolism; Agmatine - pharmacology; Animals; Arcaine; Biguanides - metabolism; Biguanides - pharmacology; Binding Sites - drug effects; Binding, Competitive; Biological and medical sciences; Dizocilpine Maleate - metabolism; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Antagonists - metabolism; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Ifenprodil; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; NMDA receptor; Pharmacology. Drug treatments; Piperidines - metabolism; Piperidines - pharmacology; Polyamine; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - metabolism; Spermidine - metabolism; Spermidine - pharmacology; Tritium; Polyamine; Ifenprodil; Excitatory amino acid receptors; NMDA receptor; Agmatine; Arcaine; Cerebral cortex; Rat; Rodentia; Central nervous system; Glutamate receptor; Vertebrata; Mammalia; Animal; Antagonist; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(02)03198-0

Ifenprodil, arcaine and agmatine have all been reported to inhibit the NMDA receptor by actions at polyamine-sites, however the specific sites with which these compounds interact is unknown. Here we used radioligand binding of [ 3H]MK-801 to a membrane preparation from rat cerebral cortex to investigate the interactions of these compounds with the NMDA receptor complex. In the absence of exogenous polyamines, agmatine reduced [ 3H]MK-801 binding only at concentrations over 500 μM, as opposed to the putative polyamine-site antagonists arcaine and ifenprodil which directly reduce ligand binding at much lower concentrations (5 μM) in the absence of polyamines. In our studies, all three compounds significantly reduced spermidine-potentiated [ 3H]MK-801 binding, however agmatine was the only compound effective at concentrations below those that produced direct inhibition of [ 3H]MK-801 binding. Under these conditions, agmatine had a K i=14.8 μM for spermidine-potentiated [ 3H]MK-801 binding and displayed characteristics of a competitive antagonist. Agmatine, as well as ifenprodil and arcaine, also displaced [ 3H]spermidine from rat cortical membranes at concentrations similar to those that were effective at reducing spermidine-potentiated [ 3H]MK-801 binding. In conclusion, these data suggest that agmatine reduces the potentiating effects of polyamines by competitive antagonism at a specific site on the NMDA receptor complex, and that these actions of agmatine differ from those of ifenprodil and arcaine.