NMDA Receptor Glycine Site Antagonists

Glycine is a co-agonist of glutamate at the NMDA receptor, increasing the affinity of the receptor for the endogenous agonist glutamate. Hence antagonism of this binding site will also antagonise NMDA receptor function. A series of high affinity antagonists have been developed for this binding site on the NMDA receptor. L-701,324, L-689,560 and GV96771A all displace [ ³ H]-glycine binding with affinities below 10 nM. None of these compounds, however, display sub-type selectivity in their actions. This is likely due to the glycine binding site being located on the NR1 subunit while the glutamate binding site is on the NR2 subunits.

NMDA Receptor Polyamine Site Antagonists

Polyamines modulate NMDA receptor function. For instance, spermine stimulates NMDA receptors and increases the affinity for glycine. Conversly, it may aslo decrease the affinity of the receptor for glutamate and generate a voltage dependent inhibition of the channel. The effects of ployamine site antagonists are specific for channels containing the NR2B subunit. Hence, ployamine site antagonists would be very useful as NR2B selective ligands. The highest affinity antagonists for this site is currently Ro 25-6981 that has a binding affinity of 6 nM.

Summary

In summary, probably the most widely used and best characterised of all the NMDA receptor antagonists is still D-AP5, although new compounds are now being developed that show greater subtype selectivity such as (R)-CPPene and PBPD. The polyamine site antagonists should be very useful as NR2B selective ligands whilst the glycine site antagonists currently display the highest affinity for this receptor.