Felbamate block of recombinant N-methyl-d-aspartate receptors: selectivity for the NR2B subunit

Abstract

The anticonvulsant felbamate blocks N-methyl-D-asparate (NMDA) receptors but fails to exhibit the neurobehavioral toxicity characteristic of other NMDA receptor antagonists. To investigate the possibility that felbamate's favorable toxicity profile could be related to NMDA receptor subtype selectivity, we examined the specificity of felbamate block of recombinant NMDA receptors composed of the NR1a subunit and various NR2 subunits. Felbamate produced a rapid, concentration-dependent block of currents evoked by 50 microM NMDA and 10 microM glycine in human embryonic kidney 293 cells expressing the rat NR1a subunit, and either the NR2A, NR2B or NR2C subunits; the IC50 values for block were 2.6, 0.52 and 2.4 mM, respectively (holding potential, - 60 mV). The Hill coefficient values were < 1 and, in kinetic analyses, onset and recovery from block were well fit by double exponential functions, indicating binding to more than one blocking site on the NMDA receptor channel complex. The higher affinity of felbamate block of NMDA receptors containing the NR2B subunit could be accounted for by more rapid association and slower dissociation from these sites. We conclude that felbamate exhibits modest selectivity for NMDA receptors composed of NR1a/NR2B subunits. This selectivity could, in part, account for the more favorable clinical profile of felbamate in comparison with NMDA receptor antagonists that do not show subunit selectivity.

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Inhibition by dynorphin A Mott et al (1998). Values for eliprodil are from Avenet et al (1997), and values for felbamate are from Harty and Rogawski (2000). Values for haloperidol are from Ilyin et al (1996).…”

Diverse mechanisms of antiepileptic drugs in the development pipeline

“…However, these recording indicate that the drug may allosterically block NMDA receptors with a specific action on receptors containing the NR2B subunit. If this observation can be confirmed, lacosamide would have some similarity with felbamate, which also is a low affinity antagonist of NMDA receptors with a preference for the NR2B subunit Harty and Rogawski, 2000). Lacosamide has good oral bioavailability (~100%), linear pharmacokinetics, a half-life (~12 h) that will allow twice-daily dosing, insignificant protein binding (<1%), and its metabolites are largely eliminated by the kidney so that there are no significant interactions with other AEDs (Hovinga, 2003).…”

“…In addition, felbamate at a concentration of 100 μM has been found to block NMDA receptor mediated synaptic responses (Pugliese et al, 1996) and to inhibit NMDA receptor currents in isolated neurons (K d , ~1 mM; Rho et al, 1994;Subramaniam et al, 1995;Kuo et al, 2004). Studies with recombinant NMDA receptor subunit combinations have indicated that felbamate selectively bocks NMDA receptors composed of NR2B subunits at lower concentrations (IC 50 , 0.5 mM), than other subunit combinations Harty and Rogawski, 2000). This selectivity could contribute to the relatively low neurobehavioral toxicity of felbamate in relation to other NMDA receptor antagonists (Löscher and Rogawski, 2002).…”

Molecular Targets for Antiepileptic Drug Development

“…271 Studies with recombinant NMDA receptors have indicated that felbamate preferentially blocks NMDA receptors containing NR2B subunits. 272,273 The drug acts as an allosteric modulator of channel gating, 274 with a preferential action to stabilize the inactivated state so as to produce a usedependent block. 275 This use-dependent action may selectively inhibit NMDA receptors that are excessively activated as is believed to occur during seizure discharges.…”