Isoxazole Ionotropic Glutamate Neurotransmitters

Analogs of the excitatory neurotransmitter glutamate are potential medicinal agents for a wide variety of neurological disorders. The isoxazole glutamate derivatives represent an important class of compounds because of their receptor specificity and binding affinity. Since the discovery of (S)-2-amino-3-(3- hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) in 1980, numerous analogs built around the isoxazole scaffold have shown remarkable selectivity for specific ionotropic glutamate receptors, but strong side effects in human clinical trials have shown the need for improvement. Trends revealed by structure activity relationship and crystallographic studies indicate the role of stereochemistry may be important in uncovering the prerequisite selectivity, which would give rise to effective therapeutics for neurological dysfunction of the glutamate receptor.