Zimmerman SS , Khatri A , Garnier-Amblard EC , Mullasseril P , Kurtkaya NL , Gyoneva S , Hansen KB , Traynelis SF , Liotta DC .

ES012870 NIEHS NIH HHS , MH094525 NIMH NIH HHS, NS065371 NINDS NIH HHS , NS078873 NINDS NIH HHS , T32 GM008602 NIGMS NIH HHS , R01 NS065371 NINDS NIH HHS , F32 NS078873 NINDS NIH HHS , T32 ES012870 NIEHS NIH HHS , R21 MH094525 NIMH NIH HHS

	Figure 1. Structure of screening hit. Chemical structure of methyl 4-(1-(2-(1H-indol-3-yl)ethyl)-3-acetyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (compound 1) that was identified as a positive modulator using a fluorescence-based screen of compound libraries in a cell line expressing diheteromeric GluN1/GluN2C NMDA receptors.
	Scheme 1. Synthesis of 1H-Pyrrol-2(5H)-onesReaction conditions: PPTS, rt, 1–24 h, 2% to >99% (procedure I). Final compounds 161–180, in which either the A or B ring is replaced, were also prepared using these conditions.
	Scheme 2. Route for the Synthesis of Pyruvate DerivativesReaction conditions: (a) diethyl oxalate, NaOEt, EtOH, 0 °C to rt, 4 h, 15% to >99% (procedure II); (b) TIPSCl, imidazole, rt, 6 h, >99%; (c) diethyl oxalate, NaOEt, EtOH, 0 °C to rt, 4 h, 28% (procedure II); (d) TBAF, 0 °C to rt, 1 h, 43%.
	Scheme 3. Synthetic Routes to Access Substituted Benzaldehydes 32–41Reaction conditions: (a) 2.0 equiv NBS, (PhCOO)2, reflux, 4 h, then AgNO3, rt, 3 h, 38–63%; (b) dibutyl vinylboronate, 5 mol % (PPh3)2PdCl2, NaCO3, reflux, 2 h, 68–80%; (c) O3; then (CH3)2S, −78 °C to rt, 12 h, 60–87%; (d) i-PrMgCl, DMF, −15 °C to rt, 3 h, 70%; (e) CO(g), (PPh3)2PdCl2, NaCO3, 110 °C, 8–24% (procedure IV); (f) CH3I, K2CO3, rt, 3 h, 58%.
	Scheme 4. Routes for the Synthesis of Amides 42–44 and Esters 45–47Reaction conditions: (a) Vilsmeier reagent, aq NH3, 0 °C, 16 h, 30%; (b) R2aR2bN where R2a = H and R2b = Me or where R2a = R2b = Me, DMAP, EDCI, 0 °C to rt, 24 h, 14–51%; (c) R2I where R2 = Et or R2 = i-Pr, K2CO3, rt, 4 h, 24–87%; (d) (CH3)2NCH(Ot-Bu)2, reflux, 11/2 h, 81%.
	Scheme 5. Route to Modifications at R11Reaction conditions: (a) TMSCH2N2, rt, 5 h, 46%; (b) NH4HCO2, reflux, 3 h, 14%; (c) Ac2O, pyridine, rt, 61/2 h, 7%; (d) R11C(O)Cl where R11 = CH2CH2CH3 or R11 = CH=CH2, TEA, −30 °C, 2 h, 20–35%.
	Figure 2. Compound 1 selectively potentiates the GluN1/GluN2C response. (A) Current traces for 1 at the GluN1/GluN2A, GluN1/GluN2B, GluN1/GluN2C, and the GluN1/GluN2D receptors. (B) Compound 1 selectively potentiates the GluN1/GluN2C receptor to a fitted maximum of 275 ± 10% with an EC50 of 24 ± 2.4, n = 12. (C) The EC50 for glycine in the absence and presence of 1 is 0.20 ± 0.01 μM (n = 6) and 0.16 ± 0.02 μM (n = 4), respectively. The EC50 for glutamate in the absence and presence of 1 is 0.8 ± 0.07 μM (n = 8) and 1.2 ± 0.04 μM (n = 6), respectively. The presence of 1 did not shift the glycine or glutamate EC50 values significantly. (D) The reversal potential is −5.1 ± 0.8 mV when activated by coagonists (100 μM glutamate and 30 μM glycine) and is −5.0 ± 1.2 mV (n = 6) when the GluN1/GluN2C receptor is potentiated by 1. The reversal potential was not significantly shifted in the presence of 1, suggesting that potentiation is independent of membrane potential.
	Figure 3. Composite concentration–effect curves for 106 enantiomers. Concentration–effect curves for the enantiomers of 106 demonstrate that only one enantiomer, 106a, is active, potentiating the GluN1/GluN2C receptor to a fitted maximum of 259 ± 8% of control with an EC50 of 18 ± 0.6 μM (n = 6).

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