CGP7930 - An allosteric modulator of GABA B Rs, GABA A Rs and inwardly-rectifying potassium channels.

Autor: Hannan SB; Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. Electronic address: saadhannan@fas.harvard.edu., Penzinger R; Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK., Mickute G; Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK., Smart TG; Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. Electronic address: t.smart@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2023 Nov 01; Vol. 238, pp. 109644. Date of Electronic Publication: 2023 Jul 06.
DOI: 10.1016/j.neuropharm.2023.109644
Abstrakt: Type-A and -B GABA receptors (GABA A Rs/GABA B Rs) 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 GABA B Rs, 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 GABA B Rs but also GABA A Rs, 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 GABA B R signalling in HEK 293 cells. In male and female rat hippocampal neuron cultures, CGP7930 allosteric effects on GABA A Rs caused prolonged rise and decay times and reduced the frequency of inhibitory postsynaptic currents and potentiated GABA A R-mediated tonic inhibition. Additional comparison between predominant synaptic- and extrasynaptic-isoforms of GABA A R indicated no evident subtype selectivity for CGP7930. In conclusion, our study of CGP7930 modulation of GABA A Rs, GABA B Rs and GIRK channels, indicates this compound is unsuitable for use as a specific GABA B R PAM.
Competing Interests: Declaration of competing interest The authors declare that there are no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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