Mechanism and impact of allosteric AMPA receptor modulation by the AmpakineTM CX546

  title={Mechanism and impact of allosteric AMPA receptor modulation by the AmpakineTM CX546},
  author={Naveen Nagarajan and Christoph Quast and Andrew R. Boxall and Mohammed Shahid and Christian Rosenmund},

Targeting AMPA receptor gating processes with allosteric modulators and mutations.

Results indicate that CTZ and TCM target deactivation and agonist potency independently of desensitization, most likely by modifying agonist dissociation (koff).

Benzamide-Type AMPA Receptor Modulators Form Two Subfamilies with Distinct Modes of Action

The evidence suggests that benzamide modulators from the Ampakine family form two subgroups with different modes and sites of action, and CX516-type drugs may have the greater therapeutic utility because of their limited efficacy in prolonging synaptic responses and in attenuating receptor desensitization.

Identification of a site in GluR1 and GluR2 that is important for modulation of deactivation and desensitization.

The GluR1(S493T) mutation has a similar impairment of modulation by either cyclothiazide or CX546, indicating that some residues at the subunit interface of glutamate receptors play an important role in channel deactivation and desensitization.

Modulation of Agonist Binding to AMPA Receptors by 1-(1,4-Benzodioxan-6-ylcarbonyl)piperidine (CX546): Differential Effects across Brain Regions and GluA1–4/Transmembrane AMPA Receptor Regulatory Protein Combinations

The data suggest that variations in physiological drug efficacy, such as the 3-fold difference previously seen in recordings from hippocampus versus thalamus, may be explained by region-specific expression of GluA1–4 as well as TARPs.

Molecular mechanisms of AMPA and kainate receptor gating and its implication in synaptic transmission

It is found that GluR1/GluR2 receptor subunits do not assemble randomly, but assemble in preferential fashion as heterodimers with two identical subunits positioned on opposite sides of the tetramer.

Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data

  • M. Black
  • Biology, Psychology
  • 2004
Preclinical work on positive AMPA modulators is reviewed to suggest that positive modulation of AMPA may offer numerous therapeutic avenues for central nervous system drug discovery.

Investigation of the Functional Effects of Two Novel Ampakines in the CNS

The semi-quantitative [C]-2-deoxyglucose model was reproducible and accurate and thus could be further used to investigate the effects of the novel Ampakines, Org 26576 and Org 24448, on cerebral function.

Mechanism of glutamate receptor desensitization

Using the GluR2 AMPA-sensitive glutamate receptor, it is shown that the ligand-binding cores form dimers and that stabilization of the intradimer interface by either mutations or allosteric modulators reduces desensitization.



Effect of cyclothiazide on binding properties of AMPA-type glutamate receptors: lack of competition between cyclothiazide and GYKI 52466.

Analysis of the results with a kinetic model of the AMPA receptor suggests that cyclothiazide does not block receptor desensitization by making the desensitized state inaccessible but rather by stabilizing the active state, i.e., by increasing the affinity of the latter to a point where it becomes energetically more favorable than the desENSitized state.

Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents

  • Kahori YamadaC. Tang
  • Biology
    The Journal of neuroscience : the official journal of the Society for Neuroscience
  • 1993
A family of compounds, the benzothiadiazides, is described here that potently inhibit rapid glutamate receptor desensitization, and the actions of cyclothiazide (CYZ), the most potent of these compounds, are described in detail.

Activation Kinetics of AMPA Receptor Channels Reveal the Number of Functional Agonist Binding Sites

It is demonstrated that binding of two agonist molecules are needed to activate AMPA receptors, but the two binding sites are not identical and independent.

Hippocampal neurons exhibit cyclothiazide-sensitive rapidly desensitizing responses to kainate

Experiments on hippocampal neurons in which responses to kainate were strongly potentiated by cyclothiazide provide a powerful new tool for analysis of allosteric regulatory mechanisms at AMPA-preferring glutamate receptors.

AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to cyclothiazide.

The results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission.