Kainate Receptor Antagonists

Until recently, very few selective kainate receptor antagonists had been synthesised. The most commonly used antagonist has been NS-102, that shows a 20 fold selectivity for kainate receptors over AMPA receptors. This compound, however, suffers from serious solubility problems, and thus it's usefulness is limited. A much more useful compound is LY382884. This compound is selective for GluR5 comtaining receptor complexes and is inactive at AMPA receptors, GluR6 homomeric receptors and GluR7/KA-2 heteromers. It is interesting that this compound is closely related to LY293558, (see above), which also shows selective antagonism of GluR5 over GluR6 and GluR7/KA-2. A new antagonist UBP301, a novel willardiine derivatve, shows a nearly 30-fold selectivity for kainate over AMPA receptors in the spinal cord.

Summary

In summary, there are more pharmacological tools that are selective for AMPA receptors than for kainate receptors. These two receptor sub-types are difficult to distinguish from each other. The most commonly used antagonists, CNQX and NBQX, are now being superseded by more selective compounds such as GYKI53665 and LY382884. New developments in the synthesis of agonists has identified the willardiine derivatives as the best hope for the synthesis of subunit selective pharmacological agents as well as sub-type selective compounds. Thus kainate receptor selective agonists such as (5)-I-willardiine and antagonists like UBP301 should prove very useful in the analysis of the role of GluR5 containing kainate receptors. In addition, a further willardiine analoge, UBP282, can be used to isolate non-GluR5 containing kainate receptors as it has antagonist activity against GluR5 and AMPA receptors y.