The anticonvulsant felbamate may act as an N-methyl-D-aspartate (NMDA) receptor antagonist, but the mechanism of block has not been fully characterized. We sought to identify the sites at which felbamate exerts its NMDA receptor blocking action using radioligand binding to rat forebrain membranes and whole-cell voltage clamp and single-channel recordings from cultured rat hippocampal neurons. Equilibrium binding isotherms for [3H]dizocilpine, a channel blocking ligand, were obtained in the presence of saturating glutamate and glycine. At a concentration of 1 mM, felbamate competitively inhibited specific [3H]dizocilpine binding, indicating that felbamate interacts with the channel blocking site. At a higher concentration (3 mM), felbamate also reduced the maximal saturation binding, demonstrating an additional allosteric action. The dissociation constant (K(b)), estimated from fits to the binding isotherms, was 0.7-1.1 mM. It has been proposed that felbamate block of NMDA receptors occurs via competitive glycine site antagonism. However, the slowing of [3H]dizocilpine dissociation by felbamate, unlike the slowing produced by 7-chlorokynurenic acid, was not reversed by increasing the glycine concentration. In addition, felbamate did not reduce specific binding of [3H]5,7-dichlorokynurenic acid, a glycine site ligand. In whole-cell voltage clamp recordings of NMDA receptor currents, its blocking time constant (69 ± 0.4 msec) was substantially faster than the dissociation time constant of glycine (390 ± 23 msec), whereas the time constant for 5,7-dichlorokynurenic acid (390 ± 20 msec) was similar. These observations indicate that felbamate block of NMDA receptors does not occur by an action at the glycine site. Single-channel recordings in outside-out patches demonstrated that felbamate induced flickering of NMDA activated unitary currents, consistent with a channel blocking action, and also reduces the channel open time and burst duration, compatible with a slower form of channel block or a separate allosteric mechanism. These studies confirm that felbamate is a low potency antagonist of NMDA receptors. The drug appears to act by a channel blocking action and also possibly by distinct effects on channel gating.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1995|
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