TCN-201

TCN-201 is a selective GluN2A-containing N-methyl-D-aspartate receptor (NMDAR) antagonist with IC50 of 0.326 μM. TCN-201 displays selectivity for GluN1/GluN2A NMDARs over GluN1/GluN2B containing NMDARs, in assays using two-electrode voltage-clamp (TEVC) recordings of NMDAR currents from Xenopus laevis oocytes expressing either GluN1/GluN2A or GluN1/GluN2B NMDARs. Similar to TCN 213, the degree of inhibition produced by TCN-201 is dependent on the concentration of the GluN1-site co-agonist, glycine (or D-serine), and is independent of the glutamate concentration. In regard to glycine at 3 μM, 10 μM, and 30 μM, the IC50 values of TCN-201 are 0.446 μM, 0.746 μM, and 3.89 μM, respectively, while with D-serine at 3 μM, 10 μM, and 30 μM, the IC50 values of TCN-201 are 0.326 μM, 0.816 μM, and 1.92 μM, respectively. TCN-201 acts in a non-competitive manner but its equilibrium constant at GluN1/GluN2A NMDARs indicates TCN-201 is around 30-times more potent than TCN 213. TCN-201 shows only modest antagonism of NMDAR-mediated currents recorded from young (DIV 9-10) neurones, but gives a strong block in older cultures (DIV 15-18) or in cultures where GluN2A subunits have been over-expressed. TCN-201 antagonism of NMDAR-mediated currents shows a negative correlation with their ifenprodil sensitivity and therefore, in combination with ifenprodil, can be used to monitor, pharmacologically, the expression levels of GluN2A and GluN2B NMDAR subunits in neuronal populations.