NMDA receptor subunit‐dependent analysis of radiprodil inhibition in neonatal male rat substantia nigra dopaminergic neurons
Bangyuan Liu, Alasdair J. GibbAbstract
Background and Purpose
Radiprodil is a GluN2B subunit selective NMDA receptor negative allosteric modulator which is currently under clinical investigation as a possible anti‐epileptic drug for paediatric use. Our goal 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 neonatal male rats were used to investigate radiprodil action. Radiprodil action was analysed using a ‘hypercube’ model with explicit receptor GluN2B subunit‐dependent binding steps for agonist and antagonist and allosteric constant describing the effect of radiprodil on agonist binding and receptor channel gating and a 2nd binding site for radiprodil that may mediate partial reversal of the radiprodil inhibitory effect.
Key Results
Radiprodil produced a concentration‐dependent partial inhibition with about 40% maximum at concentrations between 30 and 100 nM. Surprisingly, at higher radiprodil concentrations, the inhibition decreased. Radiprodil (30 nM) also caused a 12% decrease in single channel current.
Conclusion and Implications
The results are described by a two‐binding site model assuming radiprodil inhibits receptor activation by binding to the GluN2B subunit whilst reducing inhibition by binding to a secondary site, which may or may not be on the receptor. We conclude that NMDA receptor allosteric modulators such as radiprodil can display a combination of inhibitory and reversal of inhibitory 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.