IDRA-21, a positive AMPA receptor modulator, inhibits synaptic and extrasynaptic NMDA receptor mediated events in cultured cerebellar granule cells.

IDRA-21 (7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide) reduces alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptors desensitisation in vitro and restores learning and cognitive impairment in vivo. In this study, we show that in cerebellar granule cells (CGCs) in culture IDRA-21 reduces N-methyl-d-aspartate receptor (NMDAR) whole-cell currents. The effect is neither competitive nor voltage-dependent. The reduction of NMDA currents is stronger at low glycine concentrations suggesting an interaction with this site. IDRA-21 shortens miniature excitatory postsynaptic currents mediated by NMDARs (NMDA-mEPSCs) in CGCs grown in low potassium with no effect on peak amplitudes. By using fast glutamate application onto CGCs nucleated patches, we found that IDRA-21 decreases both decay time constant and amplitude of the current. Experiments performed on recombinant NMDAR expressed in HEK 293 cells showed that IDRA-21 was more effective on NR1a-NR2B than NR1a-NR2A receptors highlighting a subunit selectivity of the drug. Our findings make light on a novel target for IDRA-21: NMDA receptors function is negatively modulated and the different action at the level of extrasynaptic and synaptic receptors could be ascribed to a partial selectivity for NR2B subunits.