NMDA receptor subunit-dependent analysis of radiprodil inhibition in neonatal rat substantia nigra dopaminergic neurons

Background: and Purpose : Radiprodil is a GluN2B subunit selective NMDA receptor negative allosteric modulator. It is currently under clinical investigation as a possible anti-epileptic drug for paediatric use. The goal of this study was to investigate the inhibition of dopaminergic neuron NMDA responses by radiprodil. Experimental Approach : Whole-cell and outside-out patch-clamp recordings from substantia nigra dopaminergic neurons in acute mid-brain slices from 6- to 8-day-old rats were used to investigate the concentration-dependence of radiprodil action. Radiprodil action was analysed using a new ‘hypercube’ model with explicit receptor subunit-dependent binding steps for agonists and antagonists and allosteric constants describing the effect of radiprodil on agonist binding and receptor channel gating. Key Results : As expected from previous work with the GluN2B selective inhibitor ifenprodil, radiprodil produced a concentration-dependent partial inhibition of the NMDA response with about 40% maximum inhibition in the concentration range from 30 – 100 nM. Surprisingly, at higher radiprodil concentrations, the inhibition decreased. Radiprodil (30 nM) also caused a 12% decrease in single channel current amplitude. Conclusion: and Implications : The results can be described by a two-binding site subunit-specific model that assumes radiprodil inhibits receptor activation by binding to the GluN2B subunit while reducing inhibition by binding to the GluN2D subunit of a GluN1/GluN2B/GluN2D triheteromeric receptor. We conclude that NMDA receptor allosteric modulators like radiprodil can display a combination of inhibitory and potentiating effects, depending on drug concentration and receptor subunit combinations. These properties may give some allosteric drugs a unique profile of action, which could be advantageous in some clinical circumstances.