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

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.

Automated summary

GABA receptors, particularly GABABRs, are important therapeutic targets for neurodevelopmental and neuropsychiatric disorders. However, a widely used positive allosteric modulator, CGP7930, was found to have effects on both GABABRs and GABAARs, as well as GIRK channels, making it unsuitable as a specific GABABR PAM.