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

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

  • Mol Pharm. 2023 Jul 3;20(7):3367-3379. doi: 10.1021/acs.molpharmaceut.2c01083.
Rocio K Finol-Urdaneta 1 2,  Jeffrey R McArthur 2,  Ashraf Aboelela 3 4,  Richard S Bujaroski 3 5,  Hiwa Majed 3,  Alejandra Rangel 2,  David J Adams 2,  Marie Ranson 2 3,  Michael J Kelso 2 3,  Benjamin J Buckley 2 3
Affiliations

Affiliations

  • 1 Electrophysiology Facility for Cell Phenotyping and Drug Discovery, Wollongong, New South Wales 2522, Australia.
  • 2 Illawarra Health and Medical Research Institute (IHMRI), Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • 3 School of Chemistry and Molecular Bioscience and Molecular Horizons Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sphinx University, Assiut 71515, Egypt.
  • 5 Monash Institute of Pharmaceutical Sciences, Australian Translational Medicinal Chemistry Facility (ATMCF), Monash University, Parkville, Victoria 3052, Australia.
PMID: 37260417 DOI: 10.1021/acs.molpharmaceut.2c01083
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.

Keywords

6-iodoamiloride; ASIC; ASIC inhibition; acid-sensing ion channel; amiloride; small molecule; synchropatch.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z