In:
British Journal of Pharmacology, Wiley, Vol. 176, No. 13 ( 2019-07), p. 2238-2249
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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