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

  • Br J Pharmacol. 2019 Jul;176(13):2238-2249. doi: 10.1111/bph.14671.
Baovi N Vo  1 ,  Kristopher K Abney  2 ,  Allison Anderson  1 ,  Ezequiel Marron Fernandez de Velasco  1 ,  Michael A Benneyworth  3 ,  John Scott Daniels  4 ,  Ryan D Morrison  4 ,  Corey R Hopkins  5 ,  Charles David Weaver  6 ,  Kevin Wickman  1
Affiliations
  • 1. Department of Pharmacology, University of Minnesota, Minneapolis, MN.
  • 2. School of Graduate Studies and Research, Meharry Medical College, Nashville, TN.
  • 3. Department of Neuroscience, University of Minnesota, Minneapolis, MN.
  • 4. Research and Development, Precera Bioscience, Inc., Franklin, TN.
  • 5. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE.
  • 6. Departments of Pharmacology and Chemistry, Vanderbilt University, Nashville, TN.
PMID: 30924523 DOI: 10.1111/bph.14671
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.

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