Glutamate receptors are important potential
drug targets for cognitive enhancement and the treatment of
schizophrenia in part because they are the most prevalent excitatory
neurotransmitter receptors in the vertebrate central nervous system. One approach to the application of therapeutic agents to the
AMPA subtype of
glutamate receptors is the use of allosteric modulators, which promote dimerization by binding to a dimer interface thereby reducing the degree of desensitization and deactivation.
AMPA receptors exist in two alternatively spliced variants (flip and flop) that differ in desensitization and receptor activation profiles. Most of the structural information about modulators of the
AMPA receptor targets the flip subtype. We report here the crystal structure of the flop-selective allosteric modulator, PEPA, bound to the binding domains of the GluA2 and GluA3 flop
isoforms of
AMPA receptors. Specific hydrogen bonding patterns can explain the preference for the flop
isoform. This includes a bidentate hydrogen bonding pattern between PEPA and N754 of the flop
isoforms of GluA2 and GluA3 (the corresponding position in the flip
isoform is S754). Comparison with other allosteric modulators provides a framework for the development of new allosteric modulators with preferences for either the flip or flop
isoforms. In addition to interactions with N/S754, specific interactions of the
sulfonamide with conserved residues in the binding site are characteristics of a number of allosteric modulators. These, in combination with variable interactions with five subsites on the binding surface, lead to different stoichiometries, orientations within the binding pockets, and functional outcomes.