Glutamate receptors are the most prevalent excitatory neurotransmitter receptors
in the vertebrate central nervous system and are important potential drug
targets for cognitive enhancement and the treatment of schizophrenia. Allosteric
modulators of AMPA receptors promote dimerization by binding to a dimer
interface and reducing desensitization and deactivation. The pyrrolidine
allosteric modulators, piracetam and aniracetam, were among the first of this
class of drugs to be discovered. We have determined the structure of the ligand
binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and
a corresponding structure of GluA3 with aniracetam. Both drugs bind to GluA2 and
GluA3 in a very similar manner, suggesting little subunit specificity. However,
the binding sites for piracetam and aniracetam differ considerably. Aniracetam
binds to a symmetrical site at the center of the dimer interface. Piracetam
binds to multiple sites along the dimer interface with low occupation, one of
which is a unique binding site for potential allosteric modulators. This new
site may be of importance in the design of new allosteric regulators.
