Glutamate receptors are important in the transmision of signals across the synapses between nerve cells. Isoxazoles such as Amino-Methyl-Isoxazole Propionic Acid (AMPA) have been found to be useful in the characterization of Glutamate receptor subtypes. We have obtained results in the first granting period which show promise for the efficient preparation of chiral isoxazole glutamate receptor ligands. In the current granting period we propose (1) to complete the synthesis of a defined set of C(5) functionalized AMPA analogues based on structure based design using the G1uR2 subtype binding domain, (2) prepare linked antagonists and agonists to probe the Gouaux Glutamate receptor Activation and Antagonism model and (3) prepare glutamate receptor ligands covalently linked to molecular probes to help elucidate the conformation dynamics of the intact membrane bound receptor during activation and modulation.