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

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

Baovi N Vo, Kristopher K Abney, Allison Anderson, Ezequiel Marron Fernandez de Velasco, Michael A Benneyworth, John Scott Daniels, Ryan D Morrison, Corey R Hopkins, Charles David Weaver, Kevin Wickman

Br J Pharmacol. 2019 Jul;176(13):2238-2249.

PMID: 30924523

Abstract:

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

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1443246625	ML297		1443246-62-5	Price

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