The N-methyl-D-aspartic acid (NMDA) receptor is the receptor of glutamic acid, which is the main excitatory neurotransmitter in the human brain. Specifically, NMDARs are related to the pathogenesis and development of neuropsychiatric diseases such as epilepsy, mental retardation, autism spectrum disorder, and schizophrenia. Therefore, NMDARs have become important targets for drug discovery and development. Besides, NMDAR-dependent synaptic plasticity is a powerful candidate for regulating learning and memory processes that require the hippocampus. Moreover, NMDAR consists of two essential GluN1 subunits and two additional GluN2 or GluN3 subunits.

Furthermore, GluN2A endows NMDAR containing this subunit with unique channel characteristics. The GluN2 subunit is also the main regulator of the on/off state of NMDAR. In summary, GluN2A endows NMDAR with specific electrophysiological characteristics. Meanwhile, the presence of NMDAR containing GluN2B subunits at postsynaptic density may be a necessary condition for strengthening individual synapses. There are currently four types of GluN2 subunits (A-D). The GluN2 subunit contains glutamate binding sites and displays developmental and spatially regulated expression patterns. Here, we will introduce a potentGluN2A antagonist, MPX-004.

MPX-004 is a Potent GluN2A Antagonist for Neuropsychiatric and Developmental Disorders Research.

At first, MPX-004 inhibits GluN2A-containing NMDA receptors expressed in HEK cells with an IC₅₀ of 79 nM. Nonetheless, MPX-004 has no inhibitory effect on GluN2B or GluN2D receptor-mediated responses. Importantly, MPX-004 has the potential for neuropsychiatric and developmental disorders research.

Secondly, MPX-004 inhibits NMDA receptor-mediated currents in Xenopus oocytes expressing human GluN1+GluN2A with an IC₅₀ of 198 nM. At 10 μM, MPX-004 only weakly (up to 8%) inhibits currents in oocytes expressing GluN2B, C, or D receptors or in control oocytes. Particularly, MPX-004 causes a concentration-dependent reduction in NMDA receptor-mediated fEPSPs in region CA1. This is in response to Schaffer collateral stimulation in hippocampal slices prepared from the brains of 3- to 4-week-old rats.
Thirdly, MPX-004 with 1 μM inhibits 5-HT_1B antagonist binding by 35%, 5-HT_2A agonist binding by 31%, and EP4 agonist binding by 27%. Obviously, MPX-004 has no effect on AMPA receptor-mediated synaptic currents of pyramidal neurons in slices from mouse visual cortex- currents.

Finally, MPX-004 is a potent GluN2A antagonist for neuropsychiatric and developmental disorders research.

References:

[1] Robert A Volkmann, et al. 2016 Feb 1;11(2):e0148129.