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CGP7930 - An allosteric modulator of GABABRs, GABAARs and inwardly-rectifying potassium channels

Hannan, Saad B; Penzinger, Reka; Mickute, Ginte; Smart, Trevor G; (2023) CGP7930 - An allosteric modulator of GABABRs, GABAARs and inwardly-rectifying potassium channels. Neuropharmacology , 238 , Article 109644. 10.1016/j.neuropharm.2023.109644. Green open access

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Abstract

Type-A and -B GABA receptors (GABAARs/GABABRs) control brain function and behaviour by fine tuning neurotransmission. Over-time these receptors have become important therapeutic targets for treating neurodevelopmental and neuropsychiatric disorders. Several positive allosteric modulators (PAMs) of GABARs have reached the clinic and selective targeting of receptor subtypes is crucial. For GABABRs, CGP7930 is a widely used PAM for in vivo studies, but its full pharmacological profile has not yet been established. Here, we reveal that CGP7930 has multiple effects not only on GABABRs but also GABAARs, which for the latter involves potentiation of GABA currents, direct receptor activation, and also inhibition. Furthermore, at higher concentrations, CGP7930 also blocks G protein-coupled inwardly-rectifying K+ (GIRK) channels diminishing GABABR signalling in HEK 293 cells. In male and female rat hippocampal neuron cultures, CGP7930 allosteric effects on GABAARs caused prolonged rise and decay times and reduced the frequency of inhibitory postsynaptic currents and potentiated GABAAR-mediated tonic inhibition. Additional comparison between predominant synaptic- and extrasynaptic-isoforms of GABAAR indicated no evident subtype selectivity for CGP7930. In conclusion, our study of CGP7930 modulation of GABAARs, GABABRs and GIRK channels, indicates this compound is unsuitable for use as a specific GABABR PAM.

Type: Article
Title: CGP7930 - An allosteric modulator of GABABRs, GABAARs and inwardly-rectifying potassium channels
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neuropharm.2023.109644
Publisher version: https://doi.org/10.1016/j.neuropharm.2023.109644
Language: English
Additional information: Copyright © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10173266
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