biostudies-literatureZhao YNational Institute on Alcohol Abuse and AlcoholismNIDA NIH HHSNIAAA NIH HHSNINDS NIH HHS203-215https://www.ebi.ac.uk/biostudies/studies/S-EPMC7990506biostudies-literatureUnknown42(3)G protein-gated inwardly rectifying potassium (GIRK) channels are essential regulators of cell excitability in the brain. While they are implicated in a variety of neurological diseases in both human and animal model studies, their therapeutic potential has been largely untapped. Here, we review recent advances in the development of small molecule compounds that specifically modulate GIRK channels and compare them with first-generation compounds that exhibit off-target activity. We describe the method of discovery of these small molecule modulators, their chemical features, and their effects in vivo. These studies provide a promising outlook on the future development of subunit-specific GIRK modulators to regulate neuronal excitability in a brain region-specific manner.Trends in pharmacological sciencesAdvances in Targeting GIRK Channels in Disease.PMC7990506R01 AA018734R01 NS037682R01 DA037170R21 DA025236R21 DA048623R01 DA019022Slesinger PAGameiro-Ros IZhao YGlaaser IWfalseAdvances in Targeting GIRK Channels in Disease.G protein-gated inwardly rectifying potassium (GIRK) channels are essential regulators of cell excitability in the brain. While they are implicated in a variety of neurological diseases in both human and animal model studies, their therapeutic potential has been largely untapped. Here, we review recent advances in the development of small molecule compounds that specifically modulate GIRK channels and compare them with first-generation compounds that exhibit off-target activity. We describe the method of discovery of these small molecule modulators, their chemical features, and their effects in vivo. These studies provide a promising outlook on the future development of subunit-specific GIRK modulators to regulate neuronal excitability in a brain region-specific manner.2021-01-01T00:00:00Z2021 Mar2024-11-12T10:45:31.543Z2024-11-12T10:45:31.543ZS-EPMC79905063346832210.1016/j.tips.2020.12.002