Piracetam Defines a New Binding Site for Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic Acid (AMPA) Receptors

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 both 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.

A Novel Family of Negative and Positive Allosteric Modulators of NMDA Receptors

“…In the AMPA receptor family, several positive and negative modulators have been identified. Site-directed mutagenesis and crystallography studies indicate that the inhibitory 2, 3-benzodiazepines [e.g., 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzeneamine dihydrochloride (GYKI-52466)] bind at the dimer interface formed by the ligand-binding domains (Balannik et al, 2005;Ahmed and Oswald, 2010). Also in the ligand-binding dimer interface is a binding site for the allosteric potentiator cyclothiazide (Ahmed and Oswald, 2010).…”

“…Site-directed mutagenesis and crystallography studies indicate that the inhibitory 2, 3-benzodiazepines [e.g., 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzeneamine dihydrochloride (GYKI-52466)] bind at the dimer interface formed by the ligand-binding domains (Balannik et al, 2005;Ahmed and Oswald, 2010). Also in the ligand-binding dimer interface is a binding site for the allosteric potentiator cyclothiazide (Ahmed and Oswald, 2010). Consistent with this possible location, we find that GluN2 identity of the S2 domain influences UBP512 and UBP710 potentiation, whereas the S1 domain is important for the subunit-selective inhibitory actions of UBP608.…”

Possibilities to Use a Fixed Combination of Piracetam and Cinnarizine in Neurological Practice

“…Что касается глутаматерги-ческих влияний, то пирацетам способен увеличивать плотность NMDA-рецепторов в переднем мозге у старею-щих животных и нормализовать связанную со старением повышенную аффинность L-глутамата к NMDA-рецеп-торам, что является следствием восстановления функции этих рецепторов [11]. Пирацетам также является положи-тельным аллостерическим модулятором ионотропного глутаматного рецептора АМРА [12].…”

The Speculative Neuroscience of the Future Human Brain

“…Putative mechanisms of action differ depending on the disease process being modeled and include enhanced membrane fluidity [187], increased neurotransmitter release (e.g., dopamine) [188], protective effects on specific receptors (e.g., glutamate) [189], increased blood flow [190], enhanced corticosteroid function [191], and effects on calcium channel function [192], although, this last function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells [193]. At least two actions related to its cognitive effects are that it modulates the AMPA receptor [194], a receptor for glutamate that mediates fast synaptic transmission in the brain, and improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors, which are implicated in memory processes [195]. Thus, Piracetam's mechanisms of action are complex and enigmatic.…”