The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Development of an automated screen for Kv7. 2 potassium channels and discovery of a new agonist chemotype
Open accessAbstract
To identify pore domain ligands on Kv7.2 potassium ion channels, we compared wild-type (WT) and W236L mutant Kv7.2 channels in a series of assays with previously validated and novel agonist chemotypes. Positive controls were retigabine, flupirtine, and RL-81; i.e. Kv7.2 channel activators that significantly shift voltage-dependent activation to more negative potentials (ΔV 50) at 5 µM. We identified 6 new compounds that exhibited differential enhancing activity between WT and W236L mutant channels. Whole cell patch-clamp electrophysiology studies were conducted to identify Kv7.2. Kv7.2/3, Kv7.4, and Kv7.5 selectivity. Our results validate the SyncroPatch platform and establish new structure activity relationships (SAR). Specifically, in addition to selective Kv7.2, Kv7.2/3, Kv7.4. and Kv7.5 agonists, we identified a novel chemotype, ZK-21, a 4-aminotetrahydroquinoline that is distinct from any of the previously described Kv7 channel modifiers. Using flexible receptor docking, ZK-21 was predicted to be stabilized by W236 and bind perpendicular to retigabine, burying the benzyl carbamate group into a tunnel reaching the core of the pore domain.
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Minimal substitutions can invert activity across Kv7 isoforms, enabling selective activation of Kv7.2/7.3 over Kv7.4/7.5.
“Subtype control is now tractable: minimal substitutions can invert activity across isoforms, enabling selective activation of Kv7.2/7.3 over Kv7.4/7.5 and allowing circuit-tailored effects [242,266,268].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [268]
The Patch-clamp electrophysiology studies section reports that RL-56 selectively activates Kv7.2/3 over Kv7.4 and Kv7.5 by 50- to 200-fold. It also reports that two changes in the related compound RL-71 may shift selectivity toward Kv7.4, but says the sample was too small to verify that result. Thus, the claimed inversion is more certain than the paper supports; no page number is available in our copy. (LLM, conf=0.85)
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Metadata
- Authors
- Hernandez, C. C., Tarfa, R. A., Miguel I. Limcaoco, J., Liu, R., Mondal, P., Hill, C., Duncan, K. R., Tzounopoulos, T., Stephenson, C. R. J., O'Meara, M. J., & Wipf, P.
- Affiliations
- University of Pittsburgh (US)
- University of Michigan (US)
- Corresponding author
- Wipf, Peter
- ORCID
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 71
- Pages
- 128841
- ISSN
- 0960-894X (ISSN-L)
- PMC
- PMC9469649
- OpenAlex
- W4281894445
- Cited by
- 11
- References
- 28
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 1
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 281 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Bioorganic & Medicinal Chemistry Letters (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od025203-01a1)
- National Institute of General Medical Sciences (R01GM127774)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Kv7.4, Kv7.5, retigabine, flupirtine, structure-activity relationship, voltage dependence of activation, channel selectivity
- MeSH terms
- KCNQ Potassium Channels, KCNQ2 Potassium Channel
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