Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators

Ramos-Hunter, Susan J.; Engers, Darren W.; Kaufmann, Kristian; Du, Yu; Lindsley, Craig W.; Weaver, C. David; Sulikowski, Gary A.

doi:10.1016/j.bmcl.2013.07.002

Cited by 24 publications

(22 citation statements)

References 12 publications

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“…, [82]), most of the compounds have other primary molecular targets and/or there is little evidence for Girk subtype specificity or pharmacokinetic advantages. Recently, however, a new class of subunit-selective, efficacious, potent, and direct-acting Girk channel agonists and antagonists was identified [83–85]. The prototype (ML297) is strikingly selective for Girk1-containing heteromers, and was efficacious in mice in delaying seizure onset in a maximal electroshock model of epilepsy, and preventing convulsions and lethality in a chemically-induced epilepsy model [84].…”

Section: Pharmacologic Manipulation Of Girk Channelsmentioning

confidence: 99%

New insights into the therapeutic potential of Girk channels

Luján

Velasco

Aguado

et al. 2014

Trends in Neurosciences

109

129

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G protein-dependent signaling pathways control the activity of excitable cells of the nervous system and heart, and are the targets of neurotransmitters, clinically-relevant drugs, and drugs of abuse. G protein-gated inwardly-rectifying potassium (K+) (Girk/Kir3) channels are a key effector in inhibitory signaling pathways. Girk-dependent signaling contributes to nociception and analgesia, reward-related behavior, mood, cognition, and the heart rate regulation, and has been linked to epilepsy, Down syndrome, addiction, and arrhythmias. Here, we discuss recent advances in our understanding of Girk channel structure, organization in signaling complexes, and plasticity, as well as progress on the development of subunit-selective Girk modulators. These findings offer new hope for the selective manipulation of Girk channels to treat a variety of debilitating afflictions.

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Section: Pharmacologic Manipulation Of Girk Channelsmentioning

confidence: 99%

New insights into the therapeutic potential of Girk channels

Luján

Velasco

Aguado

et al. 2014

Trends in Neurosciences

109

129

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“…The utility of urea‐containing compounds is limited due to significant pharmacokinetic liabilities including poor solubility, low brain penetration, and modest selectivity for the K ir 3.1/3.2 channel subtype (Kaufmann et al, ). An amide‐bridged K ir 3 channel activator scaffold has also been investigated, but this scaffold has failed to yield compounds that prefer K ir 3.1/3.2 over K ir 3.1/3.4 channel subtypes (Ramos‐Hunter et al, ). Furthermore, the compounds from this scaffold were lower in potency than ML297.…”

Section: Introductionmentioning

confidence: 99%

VU0810464, a non‐urea G protein‐gated inwardly rectifying K⁺ (K_ir3/GIRK) channel activator, exhibits enhanced selectivity for neuronal K_ir3 channels and reduces stress‐induced hyperthermia in mice

Abney

Anderson

et al. 2019

British J Pharmacology

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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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“…1a). 13 These compounds were shown to be the first potent and selective activators of GIRK channels bearing the GIRK1 subunit. Subtle changes to the molecular structure of ML297 resulted in the creation of potent GIRK1 channel inhibitors, an example of which is compound 1 (Fig.…”

Section: Introductionmentioning

confidence: 99%