2,3-Benzodiazepine-type AMPA receptor antagonists and their neuroprotective effects

G. Szénási, Miklos Vegh, Geza Szabo, Szabolcs Kertesz, Gabor Kapus, Mihaly Albert, Zoltan Greff, Istvan Ling, Jozsef Barkoczy, Gyula Simig, Michael Spedding, L. Hársing

Research output: Contribution to journalArticle

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Abstract

AMPA receptors are fast ligand-gated members of glutamate receptors in neuronal and many types of non-neuronal cells. The heterotetramer complexes are assembled from four subunits (GluR1-4) in region-, development- and function-selective patterns. Each subunit contains three extracellular domains (a large amino terminal domain, an agonist-binding domain and a transducer domain), and three transmembrane segments with a loop (pore forming domain), as well as the intracellular carboxy terminal tail (traffic and conductance regulatory domain). The binding of the agonist (excitatory amino acids and their derivatives) initiates conformational realignments, which transmit to the transducer domain and membrane spanning segments to gate the channel permeable to Na+, K+ and more or less to Ca2+. Several 2,3-benzodiazepines act as non-competitive antagonists of the AMPA receptor (termed also negative allosteric modulators), which are thought to bind to the transducer domains and inhibit channel gating. Analysing their effects in vitro, it has been possible to recognize a structure-activity relationship, and to describe the critical parts of the molecules involved in their action at AMPA receptors. Blockade of AMPA receptors can protect the brain from apoptotic and necrotic cell death by preventing neuronal excitotoxicity during pathophysiological activation of glutamatergic neurons. Animal experiments provided evidence for the potential usefulness of non-competitive AMPA antagonists in the treatment of human ischemic and neurodegenerative disorders including stroke, multiple sclerosis, Parkinson's disease, periventricular leukomalacia and motoneuron disease. 2,3-Benzodiazepine AMPA antagonists can protect against seizures, decrease levodopa-induced dyskinesia in animal models of Parkinson's disease demonstrating their utility for the treatment of a variety of CNS disorders.

Original languageEnglish
Pages (from-to)166-183
Number of pages18
JournalNeurochemistry International
Volume52
Issue number1
DOIs
Publication statusPublished - Jan 2008

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AMPA Receptors
Neuroprotective Agents
GABA-A Receptors
Transducers
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Benzodiazepines
Parkinson Disease
Periventricular Leukomalacia
Excitatory Amino Acid Agonists
Dyskinesias
Glutamate Receptors
Levodopa
Motor Neurons
Structure-Activity Relationship
Neurodegenerative Diseases
Multiple Sclerosis
Tail
Seizures
Cell Death
Animal Models

Keywords

  • 2,3-Benzodiazepines
  • AMPA receptors
  • Cerebral ischemia
  • Neurodegenerative disorders
  • Neuroprotection
  • Non-competitive AMPA antagonists

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

2,3-Benzodiazepine-type AMPA receptor antagonists and their neuroprotective effects. / Szénási, G.; Vegh, Miklos; Szabo, Geza; Kertesz, Szabolcs; Kapus, Gabor; Albert, Mihaly; Greff, Zoltan; Ling, Istvan; Barkoczy, Jozsef; Simig, Gyula; Spedding, Michael; Hársing, L.

In: Neurochemistry International, Vol. 52, No. 1, 01.2008, p. 166-183.

Research output: Contribution to journalArticle

Szénási, G, Vegh, M, Szabo, G, Kertesz, S, Kapus, G, Albert, M, Greff, Z, Ling, I, Barkoczy, J, Simig, G, Spedding, M & Hársing, L 2008, '2,3-Benzodiazepine-type AMPA receptor antagonists and their neuroprotective effects', Neurochemistry International, vol. 52, no. 1, pp. 166-183. https://doi.org/10.1016/j.neuint.2007.07.002
Szénási, G. ; Vegh, Miklos ; Szabo, Geza ; Kertesz, Szabolcs ; Kapus, Gabor ; Albert, Mihaly ; Greff, Zoltan ; Ling, Istvan ; Barkoczy, Jozsef ; Simig, Gyula ; Spedding, Michael ; Hársing, L. / 2,3-Benzodiazepine-type AMPA receptor antagonists and their neuroprotective effects. In: Neurochemistry International. 2008 ; Vol. 52, No. 1. pp. 166-183.
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