Toward the development of novel small-molecule GIRK channel modulators

Authors

• ST Hubbard
• SI Son
• HH Nguyen
• N Martinez
• IW Glaaser
• A Schlessinger
• A Simeonov
• A Zakharov
• PA Slesinger
• G Rai

Abstract

G-protein gated inwardly rectifying potassium (GIRK) channels are crucial for regulating resting membrane potential and neuronal excitability. Modulating GIRK channel function can lead to novel treatment approaches for neurological disorders such as substance abuse disorder, epilepsy, and ataxia. GIRK channels operate as either homotetramers (GIRK2 and GIRK4) or heterotetramers (GIRK1/GIRK2, GIRK1/GIRK4, and GIRK2/GIRK3). However, the lack of subtype-specific GIRK-targeted small molecules hampers our understanding of their biological roles and therapeutic potential in many untreatable brain disorders. While GIRK1/GIRK2 heterotetramers are prevalent in most brain regions, GIRK2 homomeric tetramers are predominantly found in the ventral tegmental area and substantia nigra dopaminergic neurons. Recent experiments underscore the significance of GIRK1 and GIRK2 channels in disease, demonstrating that excessive channel activity considerably reduces neuronal hyperexcitability, mutations in these channels lead to loss of ion selectivity and neuronal cell death, and knockout of GIRK1 and GIRK2 channels results in seizure susceptibility.

Herein, we present the development of small-molecule GIRK channel modulators through virtual screening of a large chemical library and subsequent medicinal chemistry optimization of confirmed hits. These novel activators are evaluated using a range of assays, including the thallium flux assay and manual single-cell patch clamp, with efforts focused on improving their in vitro and in vivo pharmacokinetics. The goal is to develop a CNS-penetrating lead compound to evaluate in mouse models of alcohol addiction and epilepsy.

Scientific Focus Area: Neuroscience

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