TCN-201 and glycine potencies for wild-type and mutant NMDA receptor subtypes
| NMDA receptor subtype (GluN1/GluN2X) | TCN-201 activity | Glycine activity | |||||||
|---|---|---|---|---|---|---|---|---|---|
| [glycine] (μm) | IC50 (μm) | nH | Maximum % inhibition | N | [TCN-201] (μm) | EC50 (μm) | nH | N | |
| GluN2A | 1 | 0.10 ± 0.01 | 1.2 | 100 ± 1 | 5 | 0 | 1.1 ± 0.1 | 1.4 | 7 |
| GluN2A | 3 | 0.32 ± 0.04 | 1.5 | 81 ± 1 | 25 | 10 | 150 ± 10 | 0.9 | 6 |
| GluN2A | 30 | 1.6 ± 0.2 | 2.2 | 73 ± 2 | 12 | ||||
| GluN2A | 300 | NE | 6 | ||||||
| 2A-(2D S1) | 3 | 0.23 ± 0.02 | 1.5 | 97 ± 1 | 8 | ND | |||
| 2A-(2D S2) | 3 | NE | ND | ||||||
| GluN2B | 3 | NE | 5 | 0 | 0.3 ± 0.1 | 1.2 | 6 | ||
| GluN2B | 10 | 0.6 ± 0.2 | 1.1 | 4 | |||||
| GluN2B F784V | 3 | 6.8 ± 0.4 | 1.2 | ND | 6 | 0 | 0.8 ± 0.4 | 1.2 | 4 |
| GluN2B F784V | 10 | 5.5 ± 0.5 | 1.5 | 4 | |||||
| GluN2B L783F + F784V | 3 | 4.4 ± 0.2 | 1.3 | ND | 5 | 0 | 0.6 ± 0.1 | 1.2 | 5 |
| GluN2B L783F + F784V | 10 | 9.5 ± 0.5 | 1.5 | 6 | |||||
| GluN2C | 3 | NE | 4 | ND | |||||
| GluN2D | 3 | NE | 4 | ND | |||||
| GluN2D L808V | 3 | 72% of control at 10 μm TCN-201 | 5 | ND | |||||
| 2D-(2A S1) | 3 | NE | ND | ||||||
| 2D-(2A S2) | 3 | 1.6 ± 0.1 | 2.1 | 91 ± 4 | 6 | ND | |||
| GluN2A V783L | 3 | 70% of control at 10 μm TCN-201 | 5 | 0 | 0.6 ± 0.1 | 1.4 | 3 | ||
| GluN2A V783L | 10 | 3.7 ± 0.3 | 1.3 | 4 | |||||
| GluN2A G786D | 3 | 1.4 ± 0.1 | 1.7 | 82 ± 3 | 5 | 0 | 0.4 ± 0.01 | 1.5 | 3 |
| GluN2A G786D | 10 | 22 ± 2 | 1.1 | 4 | |||||
| GluN2A E790M | 3 | 0.60 ± 0.04 | 1.4 | 90 ± 3 | 6 | 0 | 1.0 ± 0.01 | 1.4 | 6 |
| GluN2A M788I | 3 | 1.0 ± 0.1 | 1.3 | 79 ± 3 | 5 | 0 | 0.8 ± 0.1 | 1.5 | 4 |
| GluN2A T793R | 3 | 0.32 ± 0.03 | 2.2 | 94 ± 2 | 6 | 0 | 2.4 ± 0.4 | 1.5 | 6 |
| GluN2A V783A | 3 | 0.23 ± 0.02 | 1.1 | 91 ± 2 | 5 | 0 | 2.4 ± 0.1 | 1.0 | 4 |
| GluN2A V783F | 3 | 1.9 ± 0.1 | 1.8 | 80 ± 2 | 4 | 0 | 0.5 ± 0.1 | 1.3 | 5 |
| GluN2A V783W | 3 | 0.036 ± 0.003 | 1.0 | 95 ± 2 | 4 | 0 | 4.6 ± 0.2 | 1.4 | 4 |
| GluN2A V783S | 3 | 0.66 ± 0.06 | 1.4 | 89 ± 3 | 4 | 0 | 1.4 ± 0.1 | 1.3 | 4 |
| GluN2A V783T | 3 | 0.81 ± 0.06 | 1.5 | 91 ± 1 | 4 | 0 | 1.5 ± 0.1 | 1.2 | 4 |
| GluN2A V783H | 3 | 0.060 ± 0.010 | 0.9 | 93 ± 4 | 4 | 0 | 3.8 ± 0.2 | 1.4 | 4 |
| GluN2A V783D | 3 | 0.27 ± 0.01 | 1.2 | 92 ± 2 | 4 | 0 | 6.3 ± 0.7 | 1.3 | 4 |
| GluN2A P527A | 3 | 0.48 ± 0.06 | 1.4 | 91 ± 3 | 4 | 0 | 1.5 ± 0.1 | 1.2 | 6 |
| GluN2A L777A | 3 | 0.072 ± 0.017 | 1.2 | 98 ± 1 | 4 | 0 | 2.0 ± 0.1 | 1.3 | 6 |
| GluN2A L779A | 3 | 0.52 ± 0.07 | 1.3 | 88 ± 5 | 4 | 0 | 1.1 ± 0.1 | 1.3 | 6 |
| GluN2A L780A | 3 | 67% of control at 10 μm TCN-201 | 6 | 0 | 1.3 ± 0.1 | 1.1 | 6 | ||
| GluN2A Q781A | 3 | 0.78 ± 0.03 | 1.9 | 94 ± 2 | 4 | 0 | 0.6 ± 0.07 | 1.1 | 6 |
| GluN2A G786A | 3 | 1.1 ± 0.1 | 1.8 | 87 ± 3 | 5 | 0 | 0.4 ± 0.03 | 1.0 | 6 |
| GluN2A M788A | 3 | 0.62 ± 0.02 | 1.4 | 90 ± 3 | 4 | 0 | 1.1 ± 0.1 | 1.3 | 6 |
| GluN2A E789A | 3 | 0.15 ± 0.01 | 1.4 | 96 ± 1 | 4 | 0 | 4.6 ± 0.4 | 1.3 | 6 |
| GluN1 I519A | 3 | 1.1 ± 0.1 | 1.9 | 80 ± 2 | 8 | 0 | 1.5 ± 0.1 | 1.3 | 4 |
| GluN1 F754A | 3 | 0.048 ± 0.002 | 1.4 | 98 ± 1 | 4 | 0 | 2.3 ± 0.1 | 1.6 | 4 |
| GluN1 R755A | 3 | 79% of control at 10 μm TCN-201 | 4 | 0 | 4.4 ± 0.2 | 1.1 | 4 | ||
TCN-201 IC50 (±SEM) and glycine EC50 (±SEM) were determined using two-electrode voltage-clamp recordings at wild-type and mutant GluN2 subunits coexpressed with GluN1 in Xenopus oocytes (GluN1/GluN2X). The receptors were activated by 100 μm glutamate plus the indicated concentration of glycine in the presence of the indicated concentration of TCN-201. Maximal inhibition (±SEM) was calculated as control response in the absence of TCN-201 minus residual current at saturating concentrations of TCN-201 relative to control response. GluN1 mutants were coexpressed with GluN2A. NE indicates no effect at 10 μm TCN-201. ND indicates not determined. N is the number of oocytes used to generate the data, and nH is the Hill slope.