title: 2,3-benzodiazepine-type AMPA receptor antagonists and their neuroprotective effects.
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.
authors: Division of Preclinical Research, EGIS Pharmaceuticals Plc, Bokenyfoldi ut 116, 1165 Budapest, Hungary.
authors: Gábor
authors: G
authors: Szénási
authors: Miklos
authors: M
authors: Vegh
authors: Geza
authors: G
authors: Szabo
authors: Szabolcs
authors: S
authors: Kertesz
authors: Gabor
authors: G
authors: Kapus
authors: Mihaly
authors: M
authors: Albert
authors: Zoltan
authors: Z
authors: Greff
authors: Istvan
authors: I
authors: Ling
authors: Jozsef
authors: J
authors: Barkoczy
authors: Gyula
authors: G
authors: Simig
authors: Michael
authors: M
authors: Spedding
authors: Laszlo G
authors: LG
authors: Harsing
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D008745:Methylation; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D001569:Benzodiazepines