Glutamate receptors (GluRs) function as transmembrane ion channels to regulate intracellular level of ions such as calcium in control of excitatory synaptic transmission of the central nervous system. Dysfunction of these glutamate receptors has been implicated in human brain neurodegenerative diseases, including Alzheimer's, Huntington's, and Parkinson's diseases. Despite such a significant role in both the biology and pathology of the central nervous system, detailed understanding of molecular mechanisms by which subtype- or subunit-specific glutamate receptors function in cells is still lacking. The recently determined three-dimensional crystal structure of the extracellular ligand-binding core of the prototypic AMPA-subtype GluR2, in complex with its agonist, provides a new opportunity for rational design of chemical ligands that could help elucidate the underlying mechanisms and also be useful in the therapy of the neurodegenerative diseases. Here we report our recent development in structure-based functional design of chemical ligands by using nuclear magnetic resonance (NMR) spectroscopy. The NMR structure-based method enables rapid identification of small molecular chemical ligands that bind to specific sites of the target protein. These chemical compounds can be optimized for selective binding to the target protein, and linked to produce chemical ligands with high-affinity and selectivity of the AMPA-subtype glutamate receptors.