VU0810464, a non-urea G protein-gated inwardly rectifying K+ (Kir 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal Kir 3 channels and reduces stress-induced hyperthermia in mice

Background and purpose: G protein-gated inwardly rectifying K⁺ (K_ir 3) channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. Most neuronal K_ir 3 channels consist of K_ir 3.1 and K_ir 3.2 subtypes, while cardiac K_ir 3 channels consist of K_ir 3.1 and K_ir 3.4 subtypes. Previously, we identified a family of urea-containing K_ir 3 channel activators, but these molecules exhibit suboptimal pharmacokinetic properties and modest selectivity for K_ir 3.1/3.2 relative to K_ir 3.1/3.4 channels. Here, we characterize a non-urea activator, VU0810464, which displays nanomolar potency as a K_ir 3.1/3.2 activator, improved selectivity for neuronal K_ir 3 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_ir 3 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_ir 3.1-containing K_ir 3 channels, were performed to permit direct comparisons.

Key results: VU0810464 and ML297 exhibited comparable efficacy and potency as neuronal K_ir 3 channel activators, but VU0810464 was more selective for neuronal K_ir 3 channels. VU0810464, like ML297, reduced stress-induced hyperthermia in a K_ir 3-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_ir 3 channel activator with enhanced selectivity for K_ir 3.1/3.2 channels. VU0810464 may be useful for examining K_ir 3.1/3.2 channel contributions to complex behaviours and for probing the potential of K_ir 3 channel-dependent manipulations to treat neurological disorders.