Ion channel glutamate receptors are ligand-gated transmembrane proteins and form cation-conducting channels upon binding of glutamate, a neurotransmitter. The glutamate receptors are involved in brain activities such as memory and learning whereas receptor malfunction has been implicated in neurodegenerative diseases and epilepsy. Development of specific receptor inhibitors has been a long pursued strategy in the treatment of neurological diseases. Using an iterative method (i.e., systematic evolution of ligands by exponential enrichment or SELEX) and a combinatorial RNA library of a ∼10¹⁵ sequence variation, we have carried out SELEX against the GluR2Qflip glutamate receptor expressed in HEK-293 cells and identified a group of aptamers that are putative competitive inhibitors with nanomolar affinity. These aptamers are better inhibitors and drug candidates as compared with chemically synthesized inhibitors, because the synthetic inhibitors are generally water insoluble, and have cross activity in various subunits of the glutamate receptor family as well as low affinities. We are using rapid kinetic methods including a laser-pulse photolysis technique with a photolabile precursor of glutamate or caged glutamate, to characterize the structure-function relationship of the aptamers with the glutamate receptor in the microsecond-to-millisecond time domain. The novel mechanism of action of these aptamers on the GluR2Qflip glutamate receptor will be presented, together with the prediction of the unique, minimal aptamer structures.