BACKGROUND AND PURPOSE - G protein-gated inwardly rectifying K (K 3) channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. Most neuronal K 3 channels consist of K 3.1 and K 3.2 subtypes, while cardiac K 3 channels consist of K 3.1 and K 3.4 subtypes. Previously, we identified a family of urea-containing K 3 channel activators, but these molecules exhibit suboptimal pharmacokinetic properties and modest selectivity for K 3.1/3.2 relative to K 3.1/3.4 channels. Here, we characterize a non-urea activator, VU0810464, which displays nanomolar potency as a K 3.1/3.2 activator, improved selectivity for neuronal K 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 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 3.1-containing K 3 channels, were performed to permit direct comparisons.
KEY RESULTS - VU0810464 and ML297 exhibited comparable efficacy and potency as neuronal K 3 channel activators, but VU0810464 was more selective for neuronal K 3 channels. VU0810464, like ML297, reduced stress-induced hyperthermia in a K 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 3 channel activator with enhanced selectivity for K 3.1/3.2 channels. VU0810464 may be useful for examining K 3.1/3.2 channel contributions to complex behaviours and for probing the potential of K 3 channel-dependent manipulations to treat neurological disorders.
© 2019 The British Pharmacological Society.