TP003 is a non-selective benzodiazepine site agonist that induces anxiolysis via α2GABAA receptors

Autor: Elena Neumann, Uwe Rudolph, William T. Ralvenius, Mario A. Acuña, Hanns Ulrich Zeilhofer
Rok vydání: 2018
Předmět:
Zdroj: Neuropharmacology. 143:71-78
ISSN: 0028-3908
DOI: 10.1016/j.neuropharm.2018.09.026
Popis: Benzodiazepines (BDZ), which potentiate the action of GABA at four subtypes of GABA receptors (α1, α2, α3, and α5GABARs), are highly effective against anxiety disorders, but also cause severe side effects greatly limiting their clinical application. Both, preclinical studies in genetically engineered mice, and preclinical and clinical trials with subtype-selective compounds indicate that undesired effects can in principle be avoided by targeting specific GABAR subtypes. While there is general consensus that activity at α1GABARs should be avoided, controversy exists as to whether α2 or α3GABARs need to be targeted for anxiolysis. While previous experiments in GABAR point-mutated mice demonstrated a critical role of α2GABARs, studies solely relying on pharmacological approaches suggested a dominant contribution of α3GABARs. As most α1GABAR-sparing BDZ site agonists discriminate little between α2 and α3GABARs, these claims rest almost exclusively on a single compound, TP003, that has been reported to be a selective α3GABAR modulator. Here, we have revisited the in vitro pharmacological profile of TP003 and, in addition, tested TP003 in GABAR triple point-mutated mice, in which only either α1, α2, or α3GABARs were left BDZ sensitive. These experiments revealed that TP003 behaves as a partial, rather non-selective BDZ site agonist in vitro that acts in vivo through α1, α2, and α3GABARs (α5GABAR-mediated effects were not tested). With respect to anxiolysis, our results support a critical contribution of α2GABARs, but not of α3GABARs. TP003 should therefore not be considered an α3GABAR selective agent. Previously published studies using TP003 should be interpreted with caution.
Databáze: OpenAIRE
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