VU0810464, a non‐urea G protein‐gated inwardly rectifying K⁺ (K_ir3/GIRK) channel activator, exhibits enhanced selectivity for neuronal K_ir3 channels and reduces stress‐induced hyperthermia in mice

Background and Purpose

G protein‐gated inwardly rectifying K⁺ (K_ir3) channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. Most neuronal K_ir3 channels consist of K_ir3.1 and K_ir3.2 subtypes, while cardiac K_ir3 channels consist of K_ir3.1 and K_ir3.4 subtypes. Previously, we identified a family of urea‐containing K_ir3 channel activators, but these molecules exhibit suboptimal pharmacokinetic properties and modest selectivity for K_ir3.1/3.2 relative to K_ir3.1/3.4 channels. Here, we characterize a non‐urea activator, VU0810464, which displays nanomolar potency as a K_ir3.1/3.2 activator, improved selectivity for neuronal K_ir3 channels, and improved brain penetration.

Experimental Approach

We used whole‐cell electrophysiology to measure the efficacy and potency of VU0810464 in neurons and the selectivity of VU0810464 for neuronal and cardiac K_ir3 channel subtypes. We tested VU0810464 in vivo in stress‐induced hyperthermia and elevated plus maze paradigms. Parallel studies with ML297, the prototypical activator of K_ir3.1‐containing K_ir3 channels, were performed to permit direct comparisons.

Key Results

VU0810464 and ML297 exhibited comparable efficacy and potency as neuronal K_ir3 channel activators, but VU0810464 was more selective for neuronal K_ir3 channels. VU0810464, like ML297, reduced stress‐induced hyperthermia in a K_ir3‐dependent manner in mice. ML297, but not VU0810464, decreased anxiety‐related behaviour as assessed with the elevated plus maze test.

Conclusion and Implications

VU0810464 represents a new class of K_ir3 channel activator with enhanced selectivity for K_ir3.1/3.2 channels. VU0810464 may be useful for examining K_ir3.1/3.2 channel contributions to complex behaviours and for probing the potential of K_ir3 channel‐dependent manipulations to treat neurological disorders.

DOI: 10.1111/bph.14671

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