title: Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: effects of GYKI 52466 and its novel analogues.
abstract: BACKGROUND
  Although emerging number of data supports the role of glutamate receptors and the potential of their antagonists in anxiety disorders, the involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in anxiety is less well characterized.
  
  
  OBJECTIVE
  To evaluate the anxiolytic potential of 2,3-benzodiazepine (2,3BDZ) type AMPA receptor antagonists in various models of anxiety.
  
  
  METHODS
  Whole-cell currents, hippocampal field potentials, elevated plus maze (EPM), meta-chlorophenylpiperazine (mCPP)-induced anxiety model, Vogel test in rats and light-dark test (LD) in mice were used to determine AMPA/kainite receptor properties and anxiolytic-like activity of a series of 2,3BDZ-type compounds.
  
  
  RESULTS
  The reference compound GYKI 52466 was proved active in two anxiety models in non-sedative doses: minimal effective dose (MED) was especially low in EPM (0.01 mg/kg) GYKI 53405 and GYKI 53655 showed anxiolytic-like activity in two tests (EPM and mCPP). EGIS-8332 was active in EPM and LD while EGIS-9637 showed anxiolytic-like potency in EPM, mCPP and Vogel model. EGIS-10608 was the most effective compound among 2,3BDZs tested in EPM and Vogel models (MEDs are 0.01 and 2.5 mg/kg, respectively). 2,3BDZs were active in anxiety models at doses lower than those produced sedative effects. NBQX showed anxiolytic-like activity in EPM only (3 mg/kg).
  
  
  CONCLUSIONS
  The results show that non-competitive AMPA receptor antagonists can profoundly block anxiety-like behavior in rodents independently from their motor depressant activity. However, the sedative properties at higher doses might limit their therapeutic utility as new anxiolytic drugs.
authors: Division of Preclinical Research, EGIS Pharmaceuticals Plc., 10. P.O. Box 100, H-1475, Budapest, Hungary.
authors: Gábor L
authors: GL
authors: Kapus
authors: István
authors: I
authors: Gacsályi
authors: Miklos
authors: M
authors: Vegh
authors: Hajnalka
authors: H
authors: Kompagne
authors: Endre
authors: E
authors: Hegedus
authors: Csilla
authors: C
authors: Leveleki
authors: László G
authors: LG
authors: Hársing
authors: József
authors: J
authors: Barkóczy
authors: András
authors: A
authors: Bilkei-Gorzó
authors: György
authors: G
authors: Lévay
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000494:pharmacology*; D003220:Conflict, Psychological; D003627:Data Interpretation, Statistical; D003975:Diazepam / Q000494:pharmacology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013687:Telencephalon / Q000166:cytology / Q000187:drug effects / Q000502:physiology
chemical_list: D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D011810:Quinoxalines; D018091:Receptors, AMPA; C061950:GYKI 52466; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001569:Benzodiazepines; D003975:Diazepam; C015068:1-(3-chlorophenyl)piperazine