Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate ^[1]. iGluRs have been divided into four subtypes on the basis of their ligand binding properties (pharmacology) and sequence similarity: AMPA receptors (GluA1/GRIA1; GluA2/GRIA2; GluA3/GRIA3; GluA4/GRIA4;), kainate receptors (GluK1/GRIK1; GluK2/GRIK2; GluK3/GRIK3; GluK4/GRIK4; GluK5/GRIK5) , NMDA receptors (GluN1/GRIN1; GluN2A/GRIN2A; GluN2B/GRIN2B; GluN2C/GRIN2C; GluN2D/GRIN2D; GluN3A/GRIN3A; GluN3B/GRIN3B) and delta receptors (GluD1/GRID1; GluD2/GRID2) ^[2].

iGluRs are tetramers (they are formed of four subunits). All subunits have a shared architecture with four domain layers: two extracellular clamshell domains called the N-terminal domain (NTD) and ligand-binding domain (LBD; which binds glutamate), the transmembrane domain (TMD) that forms the ion channel, and an intracellular C-terminal domain (CTD) ^[3].

The blue sphere in the 3D structure viewer (PDB: 8FWS) was the binding site of competitive antagonist DNQX. The two carbonyl groups of DNQX formed hydrogen bonds to R523 and the backbone amide of A518. The DNQX amide nitrogen makes a hydrogen bond with the backbone carbonyl of P516, while its nitro group interacts with the side-chain carboxamide of N721. The quinoxalinedione ring of DNQX lays below and parallel to the aromatic ring of Y488, maximizing their π-stacking interactions ^[4].

Extracellular H⁺ and Zn²⁺ binding site extracellular H⁺ and Zn²⁺, which inhibit NMDARs by targeting GluN1 and lead (Pb²⁺) cations, which inhibits GluN2A-containing NMDARs ^[5].

Phenylethanolamines binding sites: for non-competitive antagonists such as phenylethanolamines (e.g. ifenprodil) located at the interface with GluN1 subunits. The red sphere in the 3D structure viewer (PDB: 3QEM) forms the binding pocket of ifenprodil in GluN2B subunit containing NMDA receptor. It contains the residues of Q110, R115, F114, I111, L135, I133, S132 ^[6].

Phencyclidine (PCP) binding site: in the TMD of the NMDA receptor is of particular interest, because it should be excluded as a possible binding site for novel NMDA receptor antagonists ^[7].

Glycine site: 7-chlorokynurenic acid (7-Cl-Kyna), which is an antagonist for the glycine-binding site on GluN1 ^[8].

MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), which is an open-channel blocker of NMDAR pores, moreover a variety of substances that directly block NMDARs, including memantine and ketamine ^[11].

Glutamate recognition site: NMDARs are tetramers assembled from two GluN1 subunits, each containing a binding site for the co-agonist glycine and two GluN2A-D subunits, containing a binding site for L-glutamate in the ligand binding domain (LBD) region on each subunit. In some areas of the CNS, GluN3A and GluN3B subunits are incorporated into the tetramer ^[9]. The competitive antagonist, D-2-amino-5-phosphono-pentanoic acid (AP5), which displaces the agonist from the glutamate binding site ^[10].

Polyamine site: Polyamines, such as spermine and spermidine, exert a voltage-dependent inhibition of NMDARs at high concentrations, whereas they increase the affinity for glycine and promote NMDAR channel opening at micromolar concentrations. A number of synthetic compounds can be exploited to investigate the physiological role of NMDARs with no need for genetic manipulation ^[11].

The red sphere in the 3D structure viewer (PDB: 8FWS) was the binding site of positive allosteric modulator (BPAM344) in GluK2 kainate receptor. Their binding involves residues K531, P532, F533, T535, L783, and Q786 of one subunit and I519, P532, T535, S761, K762, and G763 of the other subunit. Except for one hydrogen bond, which links hydrogen of the BPAM344 sulfonamide nitrogen to the backbone oxygen of P532, BPAM344 binding is mediated by weak van der Waals forces, similar to BPAM344 binding to the isolated GluK1 LBD ^[12] The green sphere in the 3D structure viewer (PDB: 8FWS) was the binding site of negative allosteric modulator drug perampanel (PMP). The majority of interactions between PMP and the GluK2 hydrophobic extracellular collar binding pocket were mediated by weak van der Waals forces that involved residues N549, P550, F555, N557, P558, Y651, L655, F658, and L659 in subunit A (or C) as well as A812, S813, and A814 in subunit B (or D) and S650 in subunit D (or B) ^[13].

Traxoprodil: An allosteric, non-competitive binding site has also been identified in the N-terminal domain of NR2B. Agents which bind selectively at this site, such as Traxoprodil, exhibited a sustained antidepressant response and improved side effect profile in human clinical trials as an i.v. drug ^[14]. However, development of drugs from this class has been hindered by low bioavailability, poor pharmacokinetics, and lack of selectivity against other pharmacological targets including the hERG ion channel. GYKI-52466 is partially stabilized in the collar through a π-bond stack where GYKI-52466 is sandwiched between Phe623 at the top of the M3 helix and Pro520 on the pre-M1 helix ^[15].

The binding site of SAGE-718 on the channel is likely to overlap with that of 24(S)-HC, with structural determinants including residues in the transmembrane domain of both GluN1 and GluN2 receptor subunits ^[16].