Monna, a potent and selective blocker for transmembrane protein with unknown function 16/anoctamin-1

Soo Jin Oh, Seok Jin Hwang, Jonghoon Jung, Kuai Yu, Jeongyeon Kim, Jung Yoon Choi, H. Criss Hartzell, Eun Joo Roh, Changjoon Lee

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52 Citations (Scopus)

Abstract

Transmembrane protein with unknown function 16/anoctamin-1 (ANO1) is a protein widely expressed in mammalian tissues, and it has the properties of the classic calcium-activated chloride channel (CaCC). This protein has been implicated in numerous major physiological functions. However, the lack of effective and selective blockers has hindered a detailed study of the physiological functions of this channel. In this study, we have developed a potent and selective blocker for endogenous ANO1 in Xenopus laevis oocytes (xANO1) using a drug screening method we previously established (Oh et al., 2008). We have synthesized a number of anthranilic acid derivatives and have determined the correlation between biological activity and the nature and position of substituents in these derived compounds. A structure-activity relationship revealed novel chemical classes of xANO1 blockers. The derivatives contain a-NO2 group on position 5 of a naphthyl group-substituted anthranilic acid, and they fully blocked xANO1 chloride currents with an IC 50<10 μM. The most potent blocker, N-((4-methoxy)-2-naphthyl)- 5-nitroanthranilic acid (MONNA), had an IC50 of 0.08 μM for xANO1. Selectivity tests revealed that other chloride channels such as bestrophin-1, chloride channel protein 2, and cystic fibrosis transmembrane conductance regulator were not appreciably blocked by 10∼30 μM MONNA. The potent and selective blockers for ANO1 identified here should permit pharmacological dissection of ANO1/CaCC function and serve as potential candidates for drug therapy of related diseases such as hypertension, cystic fibrosis, bronchitis, asthma, and hyperalgesia.

Original languageEnglish
Pages (from-to)726-735
Number of pages10
JournalMolecular Pharmacology
Volume84
Issue number5
DOIs
Publication statusPublished - 2013 Nov 1

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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    Oh, S. J., Hwang, S. J., Jung, J., Yu, K., Kim, J., Choi, J. Y., Hartzell, H. C., Roh, E. J., & Lee, C. (2013). Monna, a potent and selective blocker for transmembrane protein with unknown function 16/anoctamin-1. Molecular Pharmacology, 84(5), 726-735. https://doi.org/10.1124/mol.113.087502