Background and Purpose: G protein-gated inwardly rectifying K+ (Kir3) channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. Most neuronal Kir3 channels consist of Kir3.1 and Kir3.2 subtypes, while cardiac Kir3 channels consist of Kir3.1 and Kir3.4 subtypes. Previously, we identified a family of urea-containing Kir3 channel activators, but these molecules exhibit suboptimal pharmacokinetic properties and modest selectivity for Kir3.1/3.2 relative to Kir3.1/3.4 channels. Here, we characterize a non-urea activator, VU0810464, which displays nanomolar potency as a Kir3.1/3.2 activator, improved selectivity for neuronal Kir3 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 Kir3 channel subtypes. We tested VU0810464 in vivo in stress-induced hyperthermia and elevated plus maze paradigms. Parallel studies with ML297, the prototypical activator of Kir3.1-containing Kir3 channels, were performed to permit direct comparisons. Key Results: VU0810464 and ML297 exhibited comparable efficacy and potency as neuronal Kir3 channel activators, but VU0810464 was more selective for neuronal Kir3 channels. VU0810464, like ML297, reduced stress-induced hyperthermia in a Kir3-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 Kir3 channel activator with enhanced selectivity for Kir3.1/3.2 channels. VU0810464 may be useful for examining Kir3.1/3.2 channel contributions to complex behaviours and for probing the potential of Kir3 channel-dependent manipulations to treat neurological disorders.
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