Quantification of the Mg2+-induced potency shift of amantadine and memantine voltage-dependent block in human recombinant GluN1/GluN2A NMDARs.
Clinically, amantadine and memantine are drugs whose therapeutic utility is linked to their ability to block N-methyl-D-aspartate receptors (NMDARs) in a voltage-dependent manner. Nevertheless many studies that have characterized the pharmacological actions of amantadine and memantine have done so in the absence of physiological levels of Mg(2+) ions. This study quantifies the extent to which Mg(2+) alters the potency of the block produced by both amantadine and memantine at human recombinant GluN1/GluN2A NMDARs. Human recombinant GluN1/GluN2A NMDARs were expressed in Xenopus laevis oocytes and two-electrode voltage-clamp recordings were made at -80, -60 and -40 mV to quantify amantadine and memantine block in the absence and presence of Mg(2+). Amantadine and memantine blocked human GluN1/GluN2A NMDARs in a voltage-dependent manner with IC(50) values (at -80 mV) of 49 ± 6 μM (n = 7) and 1.0 ± 0.3 μM (n = 7), respectively. In the presence of Mg(2+) (1mM) the equivalent IC(50) values were 165 ± 10 μM (n=6) and 6.6 ± 0.3 μM (n = 5). Similarly in the presence of amantadine or memantine the potency of Mg(2+) in blocking GluN1/GluN2A NMDARs was reduced. The decrease in the potencies of both amantadine and memantine in the presence of physiological concentrations of Mg(2+) indicates that other targets (e.g. α7-nicotinic acetylcholine receptors and 5-HT(3) receptors) in addition to NMDARs may well be sites of the therapeutic action of these channel blockers.
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
H J
HJ
Otton
A
A
Lawson McLean
M A
MA
Pannozzo
C H
CH
Davies
D J A
DJ
Wyllie
D000547:Amantadine / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008274:Magnesium / Q000494:pharmacology*; D008559:Memantine / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014982:Xenopus laevis
D000547:Amantadine; D008274:Magnesium; D008559:Memantine; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins