Application of hexachlorophene in preparation of voltage-gated potassium channel agonist

A technology of agonist and hexachlorophene, applied in the field of application in the preparation of antiarrhythmic drugs and antiepileptic drugs

Active Publication Date: 2014-02-12
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Abstract
  • Description
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  • Application Information

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  • Application of hexachlorophene in preparation of voltage-gated potassium channel agonist
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  • Application of hexachlorophene in preparation of voltage-gated potassium channel agonist

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Effect test

Embodiment 1 6

[0042] Example 1 Hexachlorophene Enhances KCNQ1 and KCNQ1 / KCNE1 Heteromeric Channel Current

[0043] 1. Cell Culture and Transfection

[0044] Chinese Hamster Ovary (Chinese Hamster Ovary, CHO) (Cell Bank of Chinese Academy of Sciences) culture solution formula: 50 / 50DMEM / F-12 (Gibco), adding 10% fetal bovine serum (Fetal bovine serum, FBS) (Gibco, Australia), 2 mM L-glutamine (Invitrogen).

[0045] Expression of KCNQ1 channel (KCNQ1 plasmid was donated by Professor Thomas J. Jenstsch of Zentrum für Molekulare Neurobiologie, Hamburg, the sequence was sequenced and verified with the NCBI database (National Center of Biotechnology Information, NCBI, USA) by using Megalign7 (DNAStar) sequence analysis and comparison software The number NM_000218.2 (KCNQ1) in the National Center for Biotechnology Information) has the same sequence): 24 hours before transfection, it was digested with trypsin (Sigma, China) and spread in a dish with a diameter of 35 mm. Transfection using Lipofec...

Embodiment 2 6

[0058] Embodiment 2 Hexachlorophene shortens the action potential duration of cardiomyocytes

[0059] In normal cardiomyocytes, KCNQ1 / KCNE1 heteromeric channels constitute outward I Ks The current participates in the second phase / end of the plateau phase and the third phase / rapid repolarization of the action potential of cardiomyocytes, and affects the time course of the action potential of the cardiomyocytes. However, since there is no unified understanding of the formation ratio of KCNQ1 and KCNE1 in vivo, in order to investigate the hexachloride that can enhance the KCNQ1 / KCNE1 heteromeric channel expressed heterologously in Chinese hamster ovary cells at a mass ratio of 50 / 50 Whether phenol can enhance the KCNQ1 / KCNE1 heteromeric channel in the body, to investigate whether hexachlorophene can affect the whole cardiomyocyte action potential time course by enhancing the KCNQ1 / KCNE1 heteromeric channel, the inventors of the present invention will 1 μM and 3 μM hexachlorophen...

Embodiment 3 6

[0063] Example 3 Hexachlorophene rescues type I long QT syndrome mutation channel function

[0064] In the formation of a complete action potential in cardiomyocytes, different ion channels are involved, including KCNQ1, HERG, SCN5A (Bianchi, L. et al. Am J Physiol Heart Circ Physiol 2000, 279(6), H3003-11. and Hedley, P.L. Hum Mutat 2009, 30(11), 1486-511.), KCNE1, KCNE2, etc., the abnormal function of these ion channels will lead to long QT syndrome. However, among the long QT syndromes caused by these mutations, more than 50% of congenital long QT syndromes and more than 90% of acquired long QT syndromes are attenuated by KCNQ1 mutations, It is a type of long QT syndrome.

[0065] In vivo and in vitro experiments have shown that hexachlorophene, as a KCNQ1 and KCNQ1 / KCNE1 agonist, can enhance the channel current, shift the conductance voltage curve to the left, shorten the action potential duration and other pharmacological effects. In order to detect whether hexachloroph...

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Abstract

The invention provides an application of hexachlorophene in the preparation of a KCNQ agonist. In addition, the invention provides an application of the hexachlorophene in the preparation of a medicine serving as the KCNQ agonist. In the application, the KCNQ agonist can be a KCNQ1 agonist, a KCNQ1/KCNE1 agonist, a KCNQ2 agonist or KCNQ2/KCNQ3 agonist. The hexachlorophene has the effects of shortening the action potential duration and treating the arrhythmia by boosting KCNQ1/KCNE1 electric currents and promoting the repolarization of the action potential of myocardial cells. The subtype potentiation proves that the hexachlorophene is capable of enhancing KCNQ and M electric currents and has the effects of adjusting the membrane potential level by boosting KCNQ2 electric currents and KCNQ2/KCNQ3 hetero-oligomer electric currents and weakening the issuing frequency of the action potential; the application of the hexachlorophene in the preparation of medicines taking KCNQ as anti-epileptic targets is realized, and the anti-epileptic effect is achieved.

Description

technical field [0001] The present invention belongs to the field of medicines. Specifically, the present invention relates to the application of hexachlorophene in the preparation of KCNQ agonists, wherein, in the above application, the KCNQ agonists can be KCNQ1 agonists, KCNQ1 / KCNE1 agonists, KCNQ2 agonists agent or KCNQ2 / KCNQ3 agonist. In addition, the present invention also provides an application of hexachlorophene in the preparation of a medicine as a KCNQ agonist, wherein, in the above application, the KCNQ agonist can be a KCNQ1 agonist, a KCNQ1 / KCNE1 agonist, a KCNQ2 agonist agent or KCNQ2 / KCNQ3 agonist. In addition, the present invention also relates to the application of hexachlorophene in the preparation of antiarrhythmic drugs and antiepileptic drugs. Background technique [0002] Hexachlorophene (HCP), also known as mycofenol, is widely used as a local anti-inflammatory and bactericidal drug in clinical practice. Full chemical name: 2,2'-methylenebis(3,4,6-...

Claims

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Application Information

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IPC IPC(8): A61K31/055A61P9/06A61P25/08
Inventor 利民高召兵郑月明朱雪晶
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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