Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist

J Psychopharmacol. 2011 Mar;25(3):329-44. doi: 10.1177/0269881109354928. Epub 2010 Feb 15.


In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Anti-Anxiety Agents / administration & dosage
  • Anti-Anxiety Agents / adverse effects
  • Anti-Anxiety Agents / pharmacology*
  • Anxiety / drug therapy*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • GABA-A Receptor Agonists / administration & dosage
  • GABA-A Receptor Agonists / adverse effects
  • GABA-A Receptor Agonists / pharmacology*
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage
  • Heterocyclic Compounds, 4 or More Rings / adverse effects
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Hydrocarbons, Fluorinated / administration & dosage
  • Hydrocarbons, Fluorinated / adverse effects
  • Hydrocarbons, Fluorinated / pharmacology*
  • Male
  • Mice
  • Middle Aged
  • Protein Subunits
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / metabolism
  • Saimiri
  • Species Specificity
  • Time Factors
  • Young Adult


  • Anti-Anxiety Agents
  • GABA-A Receptor Agonists
  • Gabra2 protein, mouse
  • Gabra2 protein, rat
  • Gabra3 protein, mouse
  • Gabra3 protein, rat
  • Heterocyclic Compounds, 4 or More Rings
  • Hydrocarbons, Fluorinated
  • Protein Subunits
  • Receptors, GABA-A
  • TPA-023-B