TP003 is a non-selective benzodiazepine site agonist that induces anxiolysis via α2GABA A receptors.

Benzodiazepines (BDZ), which potentiate the action of GABA at four subtypes of GABA _A receptors (α1, α2, α3, and α5GABA _A Rs), 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 GABA _A R subtypes. While there is general consensus that activity at α1GABA _A Rs should be avoided, controversy exists as to whether α2 or α3GABA _A Rs need to be targeted for anxiolysis. While previous experiments in GABA _A R point-mutated mice demonstrated a critical role of α2GABA _A Rs, studies solely relying on pharmacological approaches suggested a dominant contribution of α3GABA _A Rs. As most α1GABA _A R-sparing BDZ site agonists discriminate little between α2 and α3GABA _A Rs, these claims rest almost exclusively on a single compound, TP003, that has been reported to be a selective α3GABA _A R modulator. Here, we have revisited the in vitro pharmacological profile of TP003 and, in addition, tested TP003 in GABA _A R triple point-mutated mice, in which only either α1, α2, or α3GABA _A Rs 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 α3GABA _A Rs (α5GABA _A R-mediated effects were not tested). With respect to anxiolysis, our results support a critical contribution of α2GABA _A Rs, but not of α3GABA _A Rs. TP003 should therefore not be considered an α3GABA _A R selective agent. Previously published studies using TP003 should be interpreted with caution.
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