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


Neumann, Elena; Ralvenius, William T; Acuña, Mario A; Rudolph, Uwe; Zeilhofer, Hanns Ulrich (2018). TP003 is a non-selective benzodiazepine site agonist that induces anxiolysis via α2GABA receptors. Neuropharmacology, 143:71-78.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:1 December 2018
Deposited On:04 Oct 2018 09:18
Last Modified:31 Dec 2018 08:25
Publisher:Elsevier
ISSN:0028-3908
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.neuropharm.2018.09.026
PubMed ID:30240781

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