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

Research output: Contribution to journalArticle

47 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

Fingerprint

Chloride Channels
Proteins
Cystic Fibrosis Transmembrane Conductance Regulator
Preclinical Drug Evaluations
Bronchitis
Hyperalgesia
Xenopus laevis
Structure-Activity Relationship
Cystic Fibrosis
Inhibitory Concentration 50
Oocytes
Dissection
Chlorides
Asthma
Pharmacology
Hypertension
Drug Therapy
Acids
anthranilic acid

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Monna, a potent and selective blocker for transmembrane protein with unknown function 16/anoctamin-1. / Oh, Soo Jin; Hwang, Seok Jin; Jung, Jonghoon; Yu, Kuai; Kim, Jeongyeon; Choi, Jung Yoon; Hartzell, H. Criss; Roh, Eun Joo; Lee, Changjoon.

In: Molecular Pharmacology, Vol. 84, No. 5, 01.11.2013, p. 726-735.

Research output: Contribution to journalArticle

Oh, SJ, Hwang, SJ, Jung, J, Yu, K, Kim, J, Choi, JY, Hartzell, HC, Roh, EJ & Lee, C 2013, 'Monna, a potent and selective blocker for transmembrane protein with unknown function 16/anoctamin-1', Molecular Pharmacology, vol. 84, no. 5, pp. 726-735. https://doi.org/10.1124/mol.113.087502
Oh, Soo Jin ; Hwang, Seok Jin ; Jung, Jonghoon ; Yu, Kuai ; Kim, Jeongyeon ; Choi, Jung Yoon ; Hartzell, H. Criss ; Roh, Eun Joo ; Lee, Changjoon. / Monna, a potent and selective blocker for transmembrane protein with unknown function 16/anoctamin-1. In: Molecular Pharmacology. 2013 ; Vol. 84, No. 5. pp. 726-735.
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