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

@article{Harty2000FelbamateBO,
  title={Felbamate block of recombinant N-methyl-d-aspartate receptors: selectivity for the NR2B subunit},
  author={T. Patrick Harty and Michael A. Rogawski},
  journal={Epilepsy Research},
  year={2000},
  volume={39},
  pages={47-55}
}
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The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications.
Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor.
TLDR
It is concluded that residues L643 and T647 in NR2B as well as homologous residues V644 and T648 in NR1 are the major, and very likely the exclusive, molecular determinants constituting the FBM binding site in the NMDA receptor.
Characterization of the gating conformational changes in the felbamate binding site in NMDA channels.
TLDR
It is suggested that the effects of NMDA and glycine binding coalesce or are interrelated before or at the actual activation gate, and FBM binding seems to modulate NMDA channel gating at or after this coalescing point.
Extracellular proton-modulated pore-blocking effect of the anticonvulsant felbamate on NMDA channels.
TLDR
FBM therefore acts as an opportunistic pore blocker modulated by extracellular proton, suggesting that the FBM binding site is located at the junction of a widened and a narrow part of the ion conduction pathway.
REPLY
TLDR
Felbamate is the only marketed anticonvulsant agent with unequivocal NMDA receptor blocking activity at clinically relevant concentrations and Mazarati et al. are to be commended for highlighting the potential utility of felbamate and otherNMDA receptor antagonists in the termination of status epilepticus and for protecting against the associated seizure-induced brain damage.
Felbamate is a subunit selective modulator of recombinant gamma-aminobutyric acid type A receptors expressed in Xenopus oocytes.
Mechanisms of NMDA receptor inhibition by diarylamidine compounds
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Dinazene and DAPI demonstrated tail currents and overshoots suggesting “foot‐in‐the‐door” mechanism of action, and pentamidine was partially trapped in the closed NMDA receptor channels, which can be explained by the difference in the 3D structure of compounds.
Enhanced glutamatergic transmission reduces the anticonvulsant potential of lamotrigine but not of felbamate against tonic-clonic seizures.
TLDR
It is indicated that felbamate, but not lamotrigine, effectively prevents generalized tonic-clonic seizures, also when NMDA-mediated neurotransmission is enhanced.
Letters to the Editor
TLDR
Felbamate is the only marketed anticonvulsant agent with unequivocal NMDA receptor blocking activity at clinically relevant concentrations and Mazarati et al. are to be commended for highlighting the potential utility of felbamate and otherNMDA receptor antagonists in the termination of status epilepticus and for protecting against the associated seizure-induced brain damage.
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References

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TLDR
Observations indicate that felbamate block of NMDA receptors does not occur by an action at the glycine site, and the proposed mechanism of block is not fully characterized.
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TLDR
It is suggested that felbamate interacts with a unique site on the NR2B subunit (or one formed by NR1 plusNR2B) that interacts allosterically with the NMDA/glutamate binding site, suggesting a similarity in mechanism to other noncompetitive antagonists such as ifenprodil.
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TLDR
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TLDR
It is suggested that glutamate 201 is critical for both haloperidol and CP101,606 inhibition, thus demonstrating common features in the action of these two antagonists.
Felbamate modulates the strychnine-insensitive glycine receptor
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TLDR
Glycine antagonist sites with low and intermediate affinity for [3H]CGP 61594 were detected also in situ by radioligand binding in brain areas predominantly expressing the NR2A and NR2C subunits, respectively, making this the first antagonist radiolIGand that reliably distinguishes the glycine site of NMDA receptor subtypes.
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TLDR
It is demonstrated that Ro 25-6981 is a highly selective, activity-dependent blocker of NMDA receptors that contain the NR2B subunit, which indicated a >5000-fold selectivity.
Felbamate, a novel antiepileptic drug, reverses N-methyl-D-aspartate/glycine-stimulated increases in intracellular Ca2+ concentration.
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