TY - JOUR T1 - Subtype-Selective Antagonism of<em>N</em>-Methyl-<span class="sc">d</span>-Aspartate Receptors by Felbamate: Insights into the Mechanism of Action JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 886 LP - 894 VL - 289 IS - 2 AU - Nancy W. Kleckner AU - Jill C. Glazewski AU - Chi Chiung Chen AU - Tammy D. Moscrip Y1 - 1999/05/01 UR - http://jpet.aspetjournals.org/content/289/2/886.abstract N2 - Felbamate is an anticonvulsant used in the treatment of seizures associated with Lennox-Gastaut syndrome and complex partial seizures that are refractory to other medications. Its unique clinical profile is thought to be due to an interaction withN-methyl-d-aspartate (NMDA) receptors, resulting in decreased excitatory amino acid neurotransmission. To further characterize the interaction between felbamate and NMDA receptors, recombinant receptors expressed in Xenopusoocytes were used to investigate the subtype specificity and mechanism of action. Felbamate reduced NMDA- and glycine-induced currents most effectively at NMDA receptors composed of NR1 and NR2B subunits (IC50 = 0.93 mM), followed by NR1-2C (2.02 mM) and NR1-2A (8.56 mM) receptors. The NR1-2B-selective interaction was noncompetitive with respect to the coagonists NMDA and glycine and was not dependent on voltage. Felbamate enhanced the affinity of the NR1-2B receptor for the agonist NMDA by 3.5-fold, suggesting a similarity in mechanism to other noncompetitive antagonists such as ifenprodil. However, a point mutation at position 201 (E201R) of the ε2 (mouse NR2B) subunit that affects receptor sensitivity to ifenprodil, haloperidol, and protons reduced the affinity of NR1-ε2 receptors for felbamate by only 2-fold. Furthermore, pH had no effect on the affinity of NR1-2B receptors for felbamate. We suggest that felbamate interacts with a unique site on the NR2B subunit (or one formed by NR1 plus NR2B) that interacts allosterically with the NMDA/glutamate binding site. These results suggest that the unique clinical profile of felbamate is due in part to an interaction with the NR1-2B subtype of NMDA receptor. The American Society for Pharmacology and Experimental Therapeutics ER -