Synthesis, structure-activity relationships at the GABA(A) receptor in rat brain, and differential electrophysiological profile at the recombinant human GABA(A) receptor of a series of substituted 1,2-diphenylimidazoles

J Med Chem. 2005 Apr 7;48(7):2638-45. doi: 10.1021/jm049120y.


A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate gamma-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABA(A) receptors. Many of these compounds enhanced GABA action with potencies (EC(50) = 0.19-19 muM) and efficacies (maximal efficacies of up to 640%) similar to or greater than those of anesthetics such as etomidate, propofol, and alphaxalone. Structure-activity relationship analysis revealed that the presence of an ester moiety in the imidazole ring was required for full agonist properties, while modifications made in the phenyl rings affected potency and efficacy, with ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate showing the highest potency. These compounds potentiated the [(3)H]GABA binding to rat brain membranes, suggesting a site of interaction different from that of GABA. As for etomidate, mutation of asparagine-265 in the beta2 subunit of the GABA(A) receptor into serine reduced the ability of derivative 1i to modulate the GABA function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Behavior, Animal / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Female
  • GABA-A Receptor Agonists*
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Male
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oocytes / drug effects
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Protein Subunits / genetics
  • Protein Subunits / physiology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / physiology
  • Recombinant Proteins / agonists
  • Reflex / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xenopus laevis


  • GABA-A Receptor Agonists
  • Imidazoles
  • Protein Subunits
  • Receptors, GABA-A
  • Recombinant Proteins