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Automated Patch Clamp Screening of Amiloride and 5-N,N-Hexamethyleneamiloride Analogs Identifies 6-Iodoamiloride as a Potent Acid-Sensing Ion Channel Inhibitor.

Author information

Affiliations

  • 1. Electrophysiology Facility for Cell Phenotyping and Drug Discovery, Wollongong, New South Wales 2522, Australia.
      Authors
    • Finol-Urdaneta RK 1, 2
    (1 author)
  • 2. Illawarra Health and Medical Research Institute (IHMRI), Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522, Australia.
      Authors
    • Finol-Urdaneta RK 1, 2
    • McArthur JR 2
    • Rangel A 2
    • Adams DJ 2
    • Ranson M 2, 3
    • Kelso MJ 2, 3
    • Buckley BJ 2, 3
    (7 authors)
  • 3. School of Chemistry and Molecular Bioscience and Molecular Horizons Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia.
      Authors
    • Aboelela A 3
    • Bujaroski RS 3
    • Majed H 3
    • Ranson M 2, 3
    • Kelso MJ 2, 3
    • Buckley BJ 2, 3
    (6 authors)

ORCIDs linked to this article

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Molecular Pharmaceutics, 01 Jun 2023, 20(7):3367-3379
https://doi.org/10.1021/acs.molpharmaceut.2c01083 PMID: 37260417 

This article is based on a previously available preprint.

Abstract 

Acid-sensing ion channels (ASICs) are transmembrane sensors of extracellular acidosis and potential drug targets in several disease indications, including neuropathic pain and cancer metastasis. The K+-sparing diuretic amiloride is a moderate nonspecific inhibitor of ASICs and has been widely used as a probe for elucidating ASIC function. In this work, we screened a library of 6-substituted and 5,6-disubstituted amiloride analogs using a custom-developed automated patch clamp protocol and identified 6-iodoamiloride as a potent ASIC1 inhibitor. Follow-up IC50 determinations in tsA-201 cells confirmed higher ASIC1 inhibitory potency for 6-iodoamiloride 94 (hASIC1 94 IC50 = 88 nM, cf. amiloride 11 IC50 = 1.7 μM). A similar improvement in activity was observed in ASIC3-mediated currents from rat dorsal root ganglion neurons (rDRG single-concentration 94 IC50 = 230 nM, cf. 11 IC50 = 2.7 μM). 6-Iodoamiloride represents the amiloride analog of choice for studying the effects of ASIC inhibition on cell physiology.

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Read article at publisher's site: https://doi.org/10.1021/acs.molpharmaceut.2c01083

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Funding 

Funders who supported this work.

Illawarra Health and Medical Research Institute

    National Health and Medical Research Council (1)

    Rebecca L. Cooper Medical Research Foundation (1)