VU0810464, a non-urea GIRK channel activator, exhibits enhanced selectivity for neuronal GIRK 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.