Since the NMDA receptor was first identified by the selective activation by N-methyl-D-aspartate (NMDA, see below), it has become clear that many different subtypes of this receptor could be expressed due to the multiple combinations of individual subunits. The challenge for medicinal chemists in recent years has thus been to synthesis compounds that can discriminate between these multiple sub-types. In addition to the glutamate (NMDA) binding site, there are also multiple binding sites on the NMDA receptor for modulatory compounds. Efficient NMDA receptor activation requires not only NMDA but also a co-agonist, glycine. Activation can also be modulated by the binding of polyamines. Each of the binding sites (glutamate, glycine, ployamine) has been used as a potential target for the development of both receptor and sub-type selective compounds. Many of the agonists and competitive antagonists described here have been developed by Prof. Jeff Watkins and Dr David Jane, here at Bristol and are available through Tocris Cookson. Click on the links for details of compounds that act on AMPA and mGlu receptorsCompounds named in Red are as yet commercially unavailable; click on the y symbol for a PubMed link.

NMDA Receptor Agonists

Most of the selective NMDA receptor agonists available are, not surprisingly, based on NMDA, the diagnostic ligand for these receptors. NMDA itself is an analogue of aspartate (can also act as a weak agonist at most glutamate receptors). Although this compound acts selectively at NMDA receptors, it cannot dicsriminate between receptor subtypes. Homoquinolinic acid, on the other hand, is a conformationally constrained analogue of glutamate. This compound shows higher affinity for NMDA receptors that contain NR2B and is thus the first NMDA receptor agonist to display sub-type selectivity. A radiolabelled form of homoquinolinic acid, available through Tocris Cookson, has beeen shown to selectively label regions of the brain that express NR2B-containing NMDA receptors.

Diagnostic ligand for the NMDA receptor - none selective

NMDA Receptor Competitive Antagonists

These compounds act at the glutamate binding site. (R)-AP5 is perhaps the most commonly used NMDA receptor antagonist, developed 20 years ago by Jeff Watkins. This compound shows a tendency to selectivity for NR2A and NR2B containing NMDA receptor complexes, with a 5-fold lower Ki value for NR1/NR2A over NR1/NR2D complexes. (R)-CPP-ene follows a similar pattern. However, the degree of selectivity is greater with the Ki value for NR1/NR2D complexes nearly 20-fold higher than that for NR1/NR2A receptors, although it cannot discriminate between NR2A and NR2B-containing complexes. PBPD, on the other hand is the first compound to begin to display selectivity for NR2D over NR2A and NR2C

NMDA Receptor Channel Blockers

These compounds act by binding to the pore of the NMDA receptor channel and are thus non-competitive antagonists. The highest affinity compound available to date is MK-801 with a binding affinity of 18 nM. Both Memantine and Ketamine are lower affinity antagonists. These compounds have proved very effective NMDA receptor antagonists and MK-801 has been used in a readiolabelled form to label NMDA receptor populations in brain slices. However, none of these compounds shows subunit selectivity.