mGluR1R (EC50 = 45 nM); mGluR1R (Ki = 10 nM); mGluR2R (IC50 = 108 μM); mGluR2R (Ki = 113 μM); mGluR4R (IC50 = 593 μM); mGluR4R (Ki = 112 μM)

AMPA and metabotropic glutamate receptors are both agonistic sites for Quisqualic acid. Squireic acid stimulates both mGluR4R (EC50=593 μM; Ki=112 μM) and mGluR2R (EC50=108 μM; Ki=113 μM) [1].

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mGlu1R. The proximal amino and acidic functions of glutamate 1, Quisqualic acid 2, and (S)-3,5-DHPG 3 bind similarly to the receptor. Binding to the first lobe (I) is established through a network of hydrogen bonds between the carboxylate, the amino group, and Ser165, Thr188, and Ser186 (backbone carbonyl) (Figures 1 and 2). Binding to the second lobe (II) is secured by an ionic interaction between the ammonium and Asp318 side chain function and by a cation−Π interaction 37 between this protonated group and the aromatic moiety of Tyr23619,20 (Figures 1 and 2). This positively charged group can also interact with the negative charge of Asp208 which is more distant and located in the hinge region. Moreover, the α-proton of all ligands points to the aromatic cycle of Tyr236, making a stabilizing CH−Π interaction. 38 With 1−3, we note that the distal acidic function is bound to Tyr74, Arg323, and Lys409. However, a weaker cation−Π interaction between the aromatic ring of 3 and the ammonium of Lys409 is found in place of the ionic interaction between 1 or 2 and Lys409. In 1ewk:A, three other residues, Arg78, Ser186, and Gly293, bind to the γ-carboxylate of glutamate via two water molecules which seem to play an important role in anchoring the ligand into the cleft.20 Interestingly, in our models, direct binding is observed between these residues and 2 or 3. Indeed, with (S)-3,5-DHPG 3 the 3-phenol function is bound directly to Ser186, and the 5-phenol is linked to Gly293. Similarly, the dioxo groups of quisqualate bind directly to these residues. Additional contacts between Trp110, Gly319, and ligands stabilize the complex. While glutamate 3-proS and 4-proS protons are in van der Waals contact with Trp110 H7 and a Gly319 proton, respectively, CH−Π interactions and van der Waals contacts are detected between H6 and H7 of Trp110, a Gly319 proton, and the aromatic ring of 3 (Figure 2A). With Quisqualic acid, it is noteworthy that all bindings are very well fitted, and the heterocycle binds optimally to Tyr74, Ser186, Gly293, Arg323, and Lys409 (Figure 2B). Furthermore, all atoms of the heterocycle besides N4 are in van der Waals contact with H6 or H7 from Trp110. Thus, it seems that binding to both lobes is optimized with Quisqualic acid so that the closed conformation of the LBD is best stabilized. It should also be mentioned that several couples of residues from the two lobes interact to secure the closing of the bilobate structure as Ser166−Asn235 and Trp110−Glu292 which are close to the ligand, and these are maintained with all agonists [1]

[1]. Common and Selective Molecular Determinants Involved in Metabotopic Glutamate Receptor Agonist Activity. J Med Chem. 2002 Jul 18;45(15):3171-83.

[2]. Ligands for Glutamate Receptors: Design and Therapeutic Prospects. J Med Chem. 2000 Jul 13;43(14):2609-45.

Quisqualic acid is a non-protein α-amino acid. Quisqualic acid is an agonist of two classes of excitatory amino acid receptors: one class consists of ionotropic receptors that directly control membrane channels, and the other class consists of metabolic receptors that indirectly mediate intracellular calcium mobilization. This compound is extracted from the seeds and fruits of Quisqualis chinensis. Quisqualic acid has also been reported to be present in the Chinese honeybee (Apis cerana), with relevant data available. Quisqualic acid is an agonist of two classes of excitatory amino acid receptors: one class consists of ionotropic receptors that directly control membrane channels, and the other class consists of metabolic receptors that indirectly mediate intracellular calcium mobilization. This compound is extracted from the seeds and fruits of Quisqualis chinensis. Several potent and selective metabolic glutamate receptor (mGluR) agonists have been docked to binding sites in the closed conformation of the bilobal extracellular domains of mGlu1, 2, and 4R. For mGlu1R, we selected quisquiic acid and (S)-3,5-dihydroxyphenylglycine (3,5-DHPG); for mGlu2R, we selected dicarboxycyclopropylglycine (DCG-IV), LY354740, and (S)-4-carboxyphenylglycine (4CPG); and for mGlu4R, we selected (S)-2-amino-4-phosphonobutyric acid (AP4), 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), and (S)-4-phosphonophenylglycine (PPG). The model shows that the binding mode of the glycine moiety (α-amino and α-acidic functions) is conserved, while the distal acidic function exhibits group-specific binding. The optimal agonist can achieve optimized interactions with both lobes of the binding domain. Furthermore, we describe interlobular connections around the ligand that participate in stabilizing the closed conformation of the amino-terminal domain. In summary, the docking model supports the view that stabilizing the closed state is a key step in mGluR agonist activation. [1]

C5H7N3O5

189.1262

189.038

52809-07-1

40539

White to off-white solid

2.0±0.1 g/cm3

405.9±55.0 °C at 760 mmHg

185-187ºC dec.

199.3±31.5 °C

0.0±2.1 mmHg at 25°C

1.726

-1.85

3

6

3

13

265

1

O1C(N([H])C(N1C([H])([H])[C@@]([H])(C(=O)O[H])N([H])[H])=O)=O

ASNFTDCKZKHJSW-REOHCLBHSA-N

InChI=1S/C5H7N3O5/c6-2(3(9)10)1-8-4(11)7-5(12)13-8/h2H,1,6H2,(H,9,10)(H,7,11,12)/t2-/m0/s1

(2S)-2-amino-3-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)propanoic acid

QUISQUALIC ACID; 52809-07-1; L-Quisqualic acid; (2S)-2-amino-3-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)propanoic acid; 8OC22C1B99; QUISQUALIC ACID [MI]; DTXSID20896927; 1,2,4-Oxadiazolidine-2-propanoic acid, alpha-amino-3,5-dioxo-, (S)-;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~12.5 mg/mL (~66.09 mM)
H2O : ~2 mg/mL (~10.57 mM)

Solubility in Formulation 1: ≥ 1.25 mg/mL (6.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.25 mg/mL (6.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.25 mg/mL (6.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 25 mg/mL (132.18 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)