Revisiting AMPA Receptors as an Antiepileptic Drug Target

@article{Rogawski2011RevisitingAR,
  title={Revisiting AMPA Receptors as an Antiepileptic Drug Target},
  author={Michael A. Rogawski},
  journal={Epilepsy Currents},
  year={2011},
  volume={11},
  pages={56 - 63}
}
In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA… Expand
AMPA receptors as drug targets in neurological disease – advantages, caveats, and future outlook
Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor functionExpand
Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs
TLDR
It is proposed that the inhibitors stabilize the AMPA receptor closed state by acting as wedges between the transmembrane segments, thereby preventing gating rearrangements that are necessary for ion channel opening. Expand
AMPA receptors and perampanel behind selected epilepsies: current evidence and future perspectives
TLDR
The role of AMPA receptors in the neuronal hyperexcitability underlying epilepsy, the mechanism of action and clinical experience on the anti-seizure activity of perampanel, and the rationale for targeting AMPA receptor in specific epileptic disorders are evaluated. Expand
AMPA Receptors as Therapeutic Targets for Neurological Disorders.
TLDR
Recent advances in basic biomedical research are significantly increasing knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins, and the large complex of postsynaptic proteins that interact with AMPAceptor subunits have been shown to control AMPA receptors insertion, location, pharmacology, synaptic transmission, and plasticity. Expand
Modulating AMPA Receptors for the Treatment of CNS Disorders
TLDR
The field of AMPAR ligands continues to be a dynamic area of drug discovery, with a pronounced diversification of the chemotypes explored as positive allosteric modulators in recent years. Expand
New AMPA antagonists in epilepsy
TLDR
The development of AMPAR antagonists confirms their great clinical potential and their arrival to clinical practice has been slowed down by their unfavorable pharmacokinetic profile and tolerability; however, their clinical use might be justified by their efficacy and the new drugs developed such as perampanel have been greatly ameliorated from both points of view. Expand
The AMPA receptor antagonist perampanel is a new hope in the treatment for epilepsy
TLDR
The data raised from the studies can give a hope that perampanel offers a valuable option as an adjuvant therapy for pharmacoresistant partial-onset and secondarily generalized seizures. Expand
The AMPA receptor antagonist perampanel is a new hope in the treatment for epilepsy
TLDR
The data raised from the studies can give a hope that perampanel offers a valuable option as an adjuvant therapy for pharmacoresistant partial‐onset and secondarily generalized seizures. Expand
Research advances in basic mechanisms of seizures and antiepileptic drug action.
TLDR
Development of ideas on the mechanisms of seizures and antiepileptic drugs reflects the progress in the understanding of the central nervous system physiology, particularly of neurotransmission, and an emerging role of extrasynaptic GABAA receptors, various kinds of potassium ion channels, hyperpolarization-activated cyclic nucleotide gated (HCN) channels, acid-sensing ions channels, and gap junctions in the regulation of neuronal excitability and seizures are presented. Expand
The AMPA receptor antagonist perampanel in the adjunctive treatment of partial-onset seizures: clinical trial evidence and experience
  • B. Steinhoff
  • Medicine
  • Therapeutic advances in neurological disorders
  • 2015
TLDR
Perampanel is the first-in-class orally active, selective, noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the pharmacokinetic profile offers once-daily dosing in the evening as the best route of administration. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 89 REFERENCES
AMPA receptor antagonists for the treatment of stroke.
  • T. Weiser
  • Chemistry, Medicine
  • Current drug targets. CNS and neurological disorders
  • 2005
TLDR
Targetting more than one mechanism in the excitotoxicity cascade might be a fruitful approach for the development of neuroprotective drugs. Expand
Kainate receptors in epilepsy and excitotoxicity
TLDR
Evidence that KARs are the main targets of KA to produce the epileptogenic and excitotoxic effects of K a and KA analogs is presented, and recent findings proposing K ARs as targets of antiepileptic drugs and neuroprotective agents are reported. Expand
Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents – toward an understanding of their favorable tolerability
TLDR
Current research attempting to explain the improved tolerability of low affinity NMDA receptor antagonists is reviewed, finding kinetic properties, particularly rapid blocking rate, seem to be of key importance. Expand
AMPA receptor antagonists as potential anticonvulsant drugs.
Over the last years alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathologicalExpand
Stargazin modulates AMPA receptor antagonism
TLDR
The antagonism of the competitive antagonist CNQX and the negative allosteric modulators GYKI, and CP in the absence and presence of stargazin is compared to provide further evidence that TARPs alter the conformation of pore-forming subunits and thereby affects antagonist interaction. Expand
Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines.
  • M. Rogawski
  • Medicine
  • Trends in pharmacological sciences
  • 1993
TLDR
Recent progress in the development of therapeutically useful NMDA receptor channel blockers and a new class of selective AMPA/kainate receptor antagonists, the 2,3-benzodiazepines are reviewed. Expand
The glutamate story
TLDR
Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity. Expand
Kainate receptors: Pharmacology, function and therapeutic potential
Compared to the other glutamate receptors, progress in the understanding of the functions of kainate receptors (KARs) has lagged behind, due mainly to the relative lack of specific pharmacologicalExpand
2,3-benzodiazepine AMPA antagonists.
TLDR
In vitro and in vivo pharmacological results with 2,3-benzodiazepine AMPA antagonists indicate their potential therapeutical value in treating a great variety of central nervous system diseases, of which epilepsy and neurodegenerative disorders are regarded as the most important. Expand
The involvement of excitatory amino acids in neocortical epileptogenesis: NMDA and non-NMDA receptors
TLDR
The activation of non-NMDA receptors is necessary and sufficient to induce epileptiform activity in the neocortical slices when the GABAergic inhibitory mechanism is compromised, and their partial involvement in the PDS is dependent upon the integrity of the non- NMDA mediated input. Expand
...
1
2
3
4
5
...