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. 2010 Mar 11;53(5):2197-203.
doi: 10.1021/jm901905j.

Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors

Ahmed H Ahmed  1 , Robert E Oswald
Affiliations

Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors

Ahmed H Ahmed et al. J Med Chem. .

Abstract

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.

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Figures

Figure 1
Figure 1
Structure of GluA2 bound to piracetam. (A) Position of the ligand binding domain (S1S2) dimer in the context of the full-length tetrameric receptor. Shown is the crystal structure of GluA2 bound to the antagonist, ZK200775, with the ligand binding domain of one monomer colored in shades of blue and the other colored in shades of green. Lobe 1 is the lighter color and Lobe 2 is the darker color. (B) The dimeric form of GluA2i bound to piracetam shown in two orientations. Two symmetrical sets of three binding sites are found at the dimer interface (labeled Binding Sites 1 through 3). Binding Sites 1 and 2 are partially overlapping and would be unlikely to be occupied simultaneously. (C) Details of the binding sites for piracetam showing several water molecules in the binding site and important interactions. (D) Structures of piracetam and aniracetam.
Figure 2
Figure 2
Overlay of the position of aniracetam bound to GluA2o (fluorowillardiine in the agonist binding site, 2AL5) on the structure of piracetam bound to GluA2i (glutamate in the binding site). One molecule of aniracetam is bound to a given dimer interface, but since the interface is symmetrical, two orientations are observed. One is shown with carbons colored yellow and the other with carbons colored green. The water molecules from the aniracetam structure are shown as yellow spheres. The six molecules of piracetam are shown with white carbons and the water molecules as red spheres. The binding sites for piracetam consist of two sets of three distinct sites labeled Binding Sites 1 through 3. Subsites A, B/B′, and C/C′, described previously, are shown as circles. The structure is rotated by 90° to illustrate the position of the C/C′ subsites and Piracetam Site 3. Coloring of the backbone is the same as Figure 1.
Figure 3
Figure 3
Structure of GluA3i bound to aniracetam. (A) Dimer of GluA3 S1S2 bound to glutamate and aniracetam. One copy is shown in shades of blue and the other in shades of green. Aniracetam is shown in both orientations (one with carbons in white and the other with carbons in green). The two orientations of the sidechain of S497 are shown with carbons in white in one case and green in the other. Water molecules are shown as red spheres. (B) Details of the aniracetam binding site. Only one orientation of aniracetam, with corresponding contacts is shown. The sidechain of S497 has two orientations, one that forms a water-mediated H-bond with the sidechain of K763 and the other which forms a water mediated H-bonding network with the carbonyl of K730 and aniracetam.
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