Oh, Soo-Jin Hwang, Seok Jin Jung, Jonghoon Yu, Kuai Kim, Jeongyeon Choi, Jung Yoon Hartzell, H. Criss Roh, Eun Joo Lee, C. Justin 2024-01-20T11:04:49Z 2024-01-20T11:04:49Z 2021-08-31 2013-11 0026-895X https://pubs.kist.re.kr/handle/201004/127524 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 IC50<10 mM. The most potent blocker, N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid (MONNA), had an IC50 of 0.08 mu M 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 similar to 30 mu M 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. English AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS ACTIVATED CHLORIDE CHANNEL CA2+-ACTIVATED CL K+ CHANNELS TMEM16A EXPRESSION SECRETION NEURONS MONNA, a Potent and Selective Blocker for Transmembrane Protein with Unknown Function 16/Anoctamin-1 Article 10.1124/mol.113.087502 1 MOLECULAR PHARMACOLOGY, v.84, no.5, pp.726 - 735 MOLECULAR PHARMACOLOGY 84 5 726 735 scie scopus 000325534800007 2-s2.0-84885982866 Pharmacology & Pharmacy Pharmacology & Pharmacy Article ACTIVATED CHLORIDE CHANNEL CA2+-ACTIVATED CL K+ CHANNELS TMEM16A EXPRESSION SECRETION NEURONS Anoctamin1 calcium activated anion channel xenopus oocyte