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Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects
Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819089/ https://www.ncbi.nlm.nih.gov/pubmed/35141279 http://dx.doi.org/10.3389/fmolb.2021.805594 |
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author | Qin, Wei Li, Yi-Heng Tong, Jing Wu, Jie Zhao, Dong Li, Hui-Jin Xing, Lu He, Chun-Xia Zhou, Xin Li, Peng-Quan Meng, Ge Wu, Shao-Ping Cao, Hui-Ling |
author_facet | Qin, Wei Li, Yi-Heng Tong, Jing Wu, Jie Zhao, Dong Li, Hui-Jin Xing, Lu He, Chun-Xia Zhou, Xin Li, Peng-Quan Meng, Ge Wu, Shao-Ping Cao, Hui-Ling |
author_sort | Qin, Wei |
collection | PubMed |
description | Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal structure of Kv1.5 potassium channel impeded further new drug development. Herein, with the simulated 3D structure of Kv1.5 as the drug target, a series of 3-morpholine linked aromatic amino substituted 1H-indoles as novel Kv1.5 channel inhibitors were designed and synthesized based on target–ligand interaction analysis. The synthesis route was practical, starting from commercially available material, and the chemical structures of target compounds were characterized. It was indicated that compounds T16 and T5 (100 μM) exhibited favorable inhibitory activity against the Kv1.5 channel with an inhibition rate of 70.8 and 57.5% using a patch clamp technique. All compounds did not exhibit off-target effects against other drug targets, which denoted some selectivity on the Kv1.5 channel. Interestingly, twelve compounds exhibited favorable vasodilation activity on pre-contracted arterial rings in vitro using KCl or phenylephrine (PE) by a Myograph. The vasodilation rates of compounds T16 and T4 (100 μM) even reached over 90%, which would provide potential lead compounds for both anti-AF and anti-hypertension new drug development. |
format | Online Article Text |
id | pubmed-8819089 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88190892022-02-08 Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects Qin, Wei Li, Yi-Heng Tong, Jing Wu, Jie Zhao, Dong Li, Hui-Jin Xing, Lu He, Chun-Xia Zhou, Xin Li, Peng-Quan Meng, Ge Wu, Shao-Ping Cao, Hui-Ling Front Mol Biosci Molecular Biosciences Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal structure of Kv1.5 potassium channel impeded further new drug development. Herein, with the simulated 3D structure of Kv1.5 as the drug target, a series of 3-morpholine linked aromatic amino substituted 1H-indoles as novel Kv1.5 channel inhibitors were designed and synthesized based on target–ligand interaction analysis. The synthesis route was practical, starting from commercially available material, and the chemical structures of target compounds were characterized. It was indicated that compounds T16 and T5 (100 μM) exhibited favorable inhibitory activity against the Kv1.5 channel with an inhibition rate of 70.8 and 57.5% using a patch clamp technique. All compounds did not exhibit off-target effects against other drug targets, which denoted some selectivity on the Kv1.5 channel. Interestingly, twelve compounds exhibited favorable vasodilation activity on pre-contracted arterial rings in vitro using KCl or phenylephrine (PE) by a Myograph. The vasodilation rates of compounds T16 and T4 (100 μM) even reached over 90%, which would provide potential lead compounds for both anti-AF and anti-hypertension new drug development. Frontiers Media S.A. 2022-01-24 /pmc/articles/PMC8819089/ /pubmed/35141279 http://dx.doi.org/10.3389/fmolb.2021.805594 Text en Copyright © 2022 Qin, Li, Tong, Wu, Zhao, Li, Xing, He, Zhou, Li, Meng, Wu and Cao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences Qin, Wei Li, Yi-Heng Tong, Jing Wu, Jie Zhao, Dong Li, Hui-Jin Xing, Lu He, Chun-Xia Zhou, Xin Li, Peng-Quan Meng, Ge Wu, Shao-Ping Cao, Hui-Ling Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects |
title | Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects |
title_full | Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects |
title_fullStr | Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects |
title_full_unstemmed | Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects |
title_short | Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects |
title_sort | rational design and synthesis of 3-morpholine linked aromatic-imino-1h-indoles as novel kv1.5 channel inhibitors sharing vasodilation effects |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819089/ https://www.ncbi.nlm.nih.gov/pubmed/35141279 http://dx.doi.org/10.3389/fmolb.2021.805594 |
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