Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors

Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the “hinge” in the ligand-binding core “clamshell” that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.

• Publication year

  2005

• Venue

  Journal of Neuroscience

• Publication date

  2005-09-28

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1523/JNEUROSCI.2567-05.2005PMID 16192394PMCID PMC6725607
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• AMPA Receptor Binding Cleft Mutations That Alter Affinity, Efficacy, and Recovery from Desensitization

  2005cited by this paper
• Regulation of AMPA receptor gating by ligand binding core dimers.

  2004influential reference
• Structure and function of glutamate receptor ion channels.

  2004cited by this paper
• AMPA receptor potentiators for the treatment of CNS disorders.

  2004cited by this paper
• Amino-Acid Residues Involved in Glutamate Receptor 6 Kainate Receptor Gating and Desensitization

  2003cited by this paper
• Identification of a site in GluR1 and GluR2 that is important for modulation of deactivation and desensitization.

  2003cited by this paper
• Multiple Molecular Determinants for Allosteric Modulation of Alternatively Spliced AMPA Receptors

  2003cited by this paper
• Structural basis for partial agonist action at ionotropic glutamate receptors

  2003cited by this paper
• The mechanism of action of aniracetam at synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors: indirect and direct effects on desensitization.

  2003cited by this paper
• Probing the function, conformational plasticity, and dimer-dimer contacts of the GluR2 ligand-binding core: studies of 5-substituted willardiines and GluR2 S1S2 in the crystal.

  2003influential reference
• Mechanism of glutamate receptor desensitization

  2002influential reference
• Structural mobility of the extracellular ligand-binding core of an ionotropic glutamate receptor. Analysis of NMR relaxation dynamics.

  2002cited by this paper
• The PyMOL Molecular Graphics System

  2002cited by this paper
• Mechanism of activation and selectivity in a ligand-gated ion channel: structural and functional studies of GluR2 and quisqualate.

  2002cited by this paper
• Effects of pharmacologically induced changes in NMDA-receptor activity on long-term memory in humans.

  2001cited by this paper
• Novel AMPA receptor potentiators LY392098 and LY404187: effects on recombinant human AMPA receptors in vitro.

  2001cited by this paper
• Mechanism and impact of allosteric AMPA receptor modulation by the ampakine CX546.

  2001cited by this paper
• The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses

  2001cited by this paper
• Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466.

  2000influential reference
• Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.

  2000cited by this paper
• Further additions to MolScript version 1.4, including reading and contouring of electron-density maps.

  1999cited by this paper
• The glutamate receptor ion channels.

  1999cited by this paper
• Experimental assessment of differences between related protein crystal structures.

  1999cited by this paper
• Crystallography & NMR system: A new software suite for macromolecular structure determination.

  1998cited by this paper
• The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization.

  1998cited by this paper
• Overexpression of a glutamate receptor (GluR2) ligand binding domain in Escherichia coli: application of a novel protein folding screen.

  1997cited by this paper
• Electron-density map interpretation.

  1997cited by this paper
• Enhancement by an ampakine of memory encoding in humans.

  1997cited by this paper
• AMPA Receptor Flip/Flop Mutants Affecting Deactivation, Desensitization, and Modulation by Cyclothiazide, Aniracetam, and Thiocyanate

  1996cited by this paper
• PRODRG, a program for generating molecular topologies and unique molecular descriptors from coordinates of small molecules

  1996cited by this paper
• Effects of a memory-enhancing drug on DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents and synaptic transmission in hippocampus.

  1996influential reference
• Effects of a centrally active benzoylpiperidine drug on α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptor kinetics

  1996influential reference
• The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory.

  1996cited by this paper
• Effects of a centrally active benzoylpyrrolidine drug on AMPA receptor kinetics.

  1996influential reference
• AMoRe: an automated package for molecular replacement

  1994cited by this paper
• Raster3D Version 2.0. A program for photorealistic molecular graphics.

  1994cited by this paper
• A centrally active drug that modulates AMPA receptor gated currents.

  1994cited by this paper
• Free R value: a novel statistical quantity for assessing the accuracy of crystal structures

  1992cited by this paper
• Modulation of excitatory synaptic transmission by drugs that reduce desensitization at AMPA/kainate receptors.

  1991cited by this paper
• Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus.

  1991cited by this paper
• Modulation of the time course of fast EPSCs and glutamate channel kinetics by aniracetam.

  1991cited by this paper
• A program to produce both detailed and schematic plots of protein structures

  1991cited by this paper
• Improved methods for building protein models in electron density maps and the location of errors in these models.

  1991cited by this paper
• A family of AMPA-selective glutamate receptors.

  1990cited by this paper
• Molecular cloning and functional expression of glutamate receptor subunit genes.

  1990cited by this paper
• Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5

  1986cited by this paper

• Aniracetam restores the excitation-inhibition balance of neurotransmitters in the prefrontal cortex of mice with ADHD

  2026cites this paper
• TARPγ2-Derived Peptide Enhances Early-Phase Long-Term Potentiation and Impairs Memory Retention in Male Rats

  2025cites this paper
• Aniracetam Ameliorates Attention Deficit Hyperactivity Disorder Behavior in Adolescent Mice

  2025cites this paper
• Exploring novel green synthetic pathways and recent advances in pyrrole and its derivatives.

  2025cites this paper
• Load and lock: An emerging class of therapeutics that influence macromolecular dissociation.

  2025cites this paper
• Positive AMPA and Kainate Receptor Modulators and Their Therapeutic Potential in CNS Diseases: A Comprehensive Review

  2025cites this paper
• Distinct transmission sites within a synapse for strengthening and homeostasis

  2025cites this paper
• Pharmacological modulation of respiratory control: Ampakines as a therapeutic strategy.

  2024cites this paper
• Acute ampakines increase voiding function and coordination in a rat model of SCI

  2024cites this paper
• Acute ampakines increase voiding function and coordination in a rat model of SCI

  2023cites this paper
• Mechanisms of NMDA receptor regulation.

  2023cites this paper
• Crystal structure of the GluK1 ligand-binding domain with kainate and the full-spanning positive allosteric modulator BPAM538

  2023cites this paper
• Positive and negative allosteric modulation of GluK2 kainate receptors by BPAM344 and antiepileptic perampanel

  2023cites this paper
• 3,4-Dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide analogs act as potential AMPA receptor potentiators with antidepressant activity.

  2023cites this paper
• Astrocyte: A Foe or a Friend in Intellectual Disability-Related Diseases

  2022cites this paper
• Gold(I)-Catalyzed Heteroannulation of Salicylic Amides with Alkynes: Synthesis of 1,3-Benzoxazin-4-one Derivatives.

  2022cites this paper
• Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain

  2022cites this paper
• Ionotropic glutamate receptors: structure, function and dysfunction

  2022cites this paper
• Pyrrole as an Important Scaffold of Anticancer Drugs: Recent Advances.

  2022cites this paper
• Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data

  2021cites this paper
• Neuroimaging of Supraventricular Frontal White Matter in Children with Familial Attention-Deficit Hyperactivity Disorder and Attention-Deficit Hyperactivity Disorder Due to Prenatal Alcohol Exposure

  2021cites this paper
• Easy preparation of novel 3,3-dimethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide: Molecular structure, Hirshfeld surface, NCI analyses and molecular docking on AMPA receptors

  2021cites this paper
• Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors.

  2021cites this paper
• Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

  2021cites this paper
• Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential

  2021influential citation
• Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors.

  2021cites this paper
• A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke

  2021influential citation
• Structural basis for positive allosteric modulation of AMPA and kainate receptors

  2021influential citation
• Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: a long and winding road.

  2021cites this paper
• AMPA receptor trafficking and LTP: Carboxy-termini, amino-termini and TARPs

  2021cites this paper
• Hodgkin–Huxley–Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif

  2020influential citation
• Auxiliary Proteins are the Predominant Determinants of Differential Efficacy of Clinical Candidates Acting as AMPA Receptor Positive Allosteric Modulators

  2020cites this paper
• Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders.

  2020cites this paper
• Allosteric Modulators for GPCRs as a Therapeutic Alternative with High Potential in Drug Discovery

  2020cites this paper
• Nanoscale Mobility of the Apo State and TARP Stoichiometry Dictate the Gating Behavior of Alternatively Spliced AMPA Receptors.

  2019cites this paper
• Druggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain.

  2019cites this paper
• Structural biology of glutamate receptor ion channels: towards an understanding of mechanism.

  2019cites this paper
• Tarps differentially affect the pharmacology of ampakines

  2018cites this paper
• Structure, function, and allosteric modulation of NMDA receptors

  2018cites this paper
• Pyrrole: An insight into recent pharmacological advances with structure activity relationship.

  2018cites this paper
• Trafficking of Homomeric and Heteromeric Kainate Receptors with Impaired

  2018cites this paper
• Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor.

  2018cites this paper
• Enhancing Action of Positive Allosteric Modulators through the Design of Dimeric Compounds.

  2018cites this paper
• Designing a Formulation of the Nootropic Drug Aniracetam Using 2-Hydroxypropyl-β-Cyclodextrin Suitable for Parenteral Administration

  2018cites this paper
• Assembly and Trafficking of Homomeric and Heteromeric Kainate Receptors with Impaired Ligand Binding Sites

  2018cites this paper
• Positron Emission Tomography (PET) Ligand Development for Ionotropic Glutamate Receptors: Challenges and Opportunities for Radiotracer Targeting N-Methyl-d-aspartate (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA), and Kainate Receptors.

  2018cites this paper
• Oral aniracetam treatment in C57BL/6J mice without pre-existing cognitive dysfunction reveals no changes in learning, memory, anxiety or stereotypy

  2017cites this paper
• Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes.

  2017cites this paper
• Visualizing the dynamics of ionotropic glutamate receptors using atomic force microscopy

  2017influential citation
• Stabilization of protein-protein interactions in drug discovery

  2017cites this paper
• Structural and Functional Architecture of AMPA-Type Glutamate Receptors and Their Auxiliary Proteins.

  2017cites this paper
• Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors

  2017cites this paper
• A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors

  2017cites this paper
• Novel Mode of Antagonist Binding in NMDA Receptors Revealed by the Crystal Structure of the GluN1-GluN2A Ligand-Binding Domain Complexed to NVP-AAM077

  2017cites this paper
• Identification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors

  2017influential citation
• A novel NMDA receptor positive allosteric modulator that acts via the transmembrane domain.

  2017influential citation
• Modulating AMPA Receptors for the Treatment of CNS Disorders

  2017cites this paper
• Study of oral aniracetam in C 57 BL / 6 J mice without pre-existing cognitive impairments

  2017cites this paper
• Title AMPA Receptor Modulation for Enhancing Plasticity and Treating Neuropathology

  2017cites this paper
• Configurational Preference of the Glutamate Receptor Ligand Binding Domain Dimers.

  2017cites this paper
• Enthalpy-Entropy Compensation in the Binding of Modulators at Ionotropic Glutamate Receptor GluA2.

  2016influential citation
• Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure-Activity Relationship at AMPA Receptors.

  2016cites this paper
• Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.

  2016cites this paper
• Docking, characterization and investigation of β-cyclodextrin complexed with citronellal, a monoterpene present in the essential oil of Cymbopogon species, as an anti-hyperalgesic agent in chronic muscle pain model.

  2016cites this paper
• Neuropeptide cycloprolylglycine is an endogenous positive modulator of AMPA receptors

  2016cites this paper
• An unexpected reversal in the pharmacological stereoselectivity of benzothiadiazine AMPA positive allosteric modulators

  2016cites this paper
• 7-Chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-Dioxide as Positive Allosteric Modulator of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor. The End of the Unsaturated-Inactive Paradigm?

  2016cites this paper
• Dynamics and allostery of the ionotropic glutamate receptors and the ligand binding domain

  2016cites this paper
• Chronic Ampakine Treatments Stimulate Dendritic Growth and Promote Learning in Middle-Aged Rats

  2016cites this paper
• Pharmacophore analysis of positive allosteric modulators of AMPA receptors

  2016cites this paper
• AMPA Receptor Positive Allosteric Modulators: Potential for the Treatment of Neuropsychiatric and Neurological Disorders.

  2016cites this paper
• Protons Potentiate GluN1/GluN3A Currents by Attenuating Their Desensitisation

  2016cites this paper
• Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function.

  2016cites this paper
• AMPA receptor potentiators: from drug design to cognitive enhancement.

  2015cites this paper
• Novel bivalent positive allosteric modulators of AMPA receptor

  2015cites this paper
• Stabilization of Protein-Protein Interactions in chemical biology and drug discovery.

  2015cites this paper
• A novel dualistic profile of an allosteric AMPA receptor modulator identified through studies on recombinant receptors, mouse hippocampal synapses and crystal structures.

  2015cites this paper
• Rational Design of a Novel AMPA Receptor Modulator through a Hybridization Approach.

  2015cites this paper
• Structure and gating of tetrameric glutamate receptors

  2015cites this paper
• The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).

  2015cites this paper
• Three-component reaction toward polyannulated quinazolinones, benzoxazinones, and benzothiazinones.

  2015cites this paper
• Kinetic Contributions to Gating by Interactions Unique to N-methyl-d-aspartate (NMDA) Receptors*

  2015cites this paper
• Prediction of allosteric sites on protein surfaces with an elastic-network-model-based thermodynamic method.

  2014cites this paper
• Glutamate receptors: mechanistic twists and turns.

  2014cites this paper
• AMPA Receptor Modulation for Enhancing Plasticity and Treating Neuropathology

  2014cites this paper
• Functional insight into development of positive allosteric modulators of AMPA receptors.

  2014influential citation
• Conformational Mechanisms of Signaling Bias of Ion Channels

  2014cites this paper
• Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces

  2014cites this paper
• [Possible involvement of 5-HT₇ receptor in pathophysiology of affective disorders and action of antidepressant drugs].

  2014cites this paper
• Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states.

  2014cites this paper
• Antidepressant Interactions with the NMDANR 1-1 b Subunit

  2014cites this paper
• A Charge-inverting Mutation in the “Linker” Region of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Alters Agonist Binding and Gating Kinetics Independently of Allosteric Modulators*

  2014cites this paper
• Pharmacological enhancement of memory or cognition in normal subjects

  2014cites this paper
• Crosslinking the ligand‐binding domain dimer interface locks kainate receptors out of the main open state

  2013cites this paper
• Calcium-Permeable AMPA Receptors in the Nucleus Accumbens Regulate Depression-Like Behaviors in the Chronic Neuropathic Pain State

  2013cites this paper
• X-ray Crystallographic Structures as a Source of Ligand Alignment in 3D-QSAR

  2013cites this paper
• AMPA receptors mediate passive avoidance deficits induced by sleep deprivation.

  2013cites this paper
• The NMDA receptor as a target for cognitive enhancement.

  2013cites this paper
• Mechanism based approaches for rescuing and enhancing cognition

  2013cites this paper
• Current Evidence of Chinese Herbal Constituents with Effects on NMDA Receptor Blockade

  2013cites this paper