title: Characterization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine binding site of the GABAA receptor.
abstract: Benzodiazepines are among the most effective drugs for the treatment of anxiety disorders. However, their use is limited by undesired side effects, including sedation, development of tolerance, and drug abuse. The aim of this study was to evaluate the pharmacological profile of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on] in different models of anxiety and to correlate these effects with its activity in vitro. ELB139 binds with an IC(50) of 1390 nM to the flunitrazepam binding site in rat forebrain cortical membranes. In rat hippocampal neurons, ELB139 potentiated GABA-induced currents without reaching the maximum effect of diazepam, indicating a partial benzodiazepine agonism. The potentiation was antagonized by the benzodiazepine antagonist flumazenil. ELB139 (10 and 30 mg/kg p.o.) was active in three different animal models of anxiety, i.e., in the elevated plus-maze, the light and dark box, and the Vogel conflict test. The anxiolytic activity in the elevated plus-maze was almost completely reversed by flumazenil (5 mg/kg i.p.), indicating that interaction with the benzodiazepine binding site is central to the pharmacological activity. No hint of sedation was observed at the doses tested in the three anxiety models and the open field. Also, no development of tolerance was observed within 6 weeks b.i.d. treatment with ELB139 in the elevated plus-maze test. In summary, ELB139 elicits strong effects on anxiety-related behavior in rats mediated by its benzodiazepine-like activity without showing sedation or the development of tolerance, a major side effect of benzodiazepines. These characteristics make the compound a prime candidate for clinical development.
authors.affiliation: Department of Pharmacology, elbion AG, Meissner Strasse 191, D-01445 Radebeul, Germany. barbara.langen@elbion.de
authors.forename: Barbara
authors.initials: B
authors.lastname: Langen
authors.forename: Ute
authors.initials: U
authors.lastname: Egerland
authors.forename: Katrin
authors.initials: K
authors.lastname: Bernöster
authors.forename: Rita
authors.initials: R
authors.lastname: Dost
authors.forename: Klaus
authors.initials: K
authors.lastname: Unverferth
authors.forename: Chris
authors.initials: C
authors.lastname: Rundfeldt
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D003220:Conflict, Psychological; D003975:Diazepam / Q000494:pharmacology; D004361:Drug Tolerance; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D018755:GABA Agonists / Q000494:pharmacology*; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D008027:Light; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; D010880:Piperidines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C504151:1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one; D003975:Diazepam