Selective maxi-k potassium channel opener that functions under conditions of high intracellular calcium concentration, methods and uses

摘要

The present invention describes calcium sensitive and selective maxi-K potassium channel opener/activator compounds that function to open maxi-K channels under conditions of high intracellular calcium concentrations, and which do not significantly affect the opening of maxi-K channel proteins under conditions of low or physiologically normal intracellular calcium concentrations. Methods of assaying for and using such compounds are also provided. According to the invention, whole cell voltage patch-clamp studies newly demonstrated that the ability of opener compounds, e.g., fluoro-oxindoles and chloro-oxindoles, to open maxi-K channels was sensitive to the intracellular Ca2+ concentration ([Ca2+])i, i.e., more channels opened at more negative potentials. Particular fluoro-oxindole and chloro-oxindole compounds produced significant increases in whole-cell maxi-K potassium channel-mediated outward currents only in cells having higher [Ca2+]i, compared with effects in lower [Ca2+]i. Such compounds provide Ca2+-sensitive and selective openers of maxi-K channels which show maximum effectiveness under conditions of increased [Ca2+]i and, as such, provide treatments for diseases and disorders in which cells undergo, or are subject to, traumatic stress due to high internal calcium levels, such as stroke.

机译：本发明描述了钙敏感性和选择性的maxi-K钾通道开放剂/活化剂化合物，其在高细胞内钙浓度的条件下起作用以打开maxi-K通道，并且在以下条件下不显着影响maxi-K通道蛋白的开放。低或生理上正常的细胞内钙浓度。还提供了测定和使用此类化合物的方法。根据本发明，全细胞电压膜片钳研究最近证明，开放剂化合物例如氟代-羟吲哚和氯代-羟吲哚打开maxi-K通道的能力对细胞内Ca 2+浓度敏感（[ Ca 2 +]）i，即更多的通道以更多的负电势打开。特定的氟代-羟吲哚和氯代-羟吲哚化合物仅在具有较高[Ca 2+] i的细胞中产生全细胞maxi-K钾通道介导的外向电流的显着增加，而在较低的[Ca 2+]中则产生作用]一世。此类化合物可提供maxi-K通道对Ca 2+敏感的选择性开放剂，在[Ca 2+] i升高的条件下显示出最大的功效，因此可为细胞经历的疾病和失调提供治疗，或由于内部高钙水平（例如中风）而遭受创伤性压力。

著录项

公开/公告号JP2004511457A

专利类型
公开/公告日2004-04-15

原文格式PDF
申请/专利权人ブリストル－マイヤーズ　スクイブ　カンパニー;
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申请/专利号JP20020534257
发明设计人バレンティン・ケイ・グリブコフ;デブラ・ジェイ・ポスト－マンソン;サリタ・ダブリュー・イェオラ;クリストファー・ジー・ボイサード;ピヤセナ・ヘワワサム;
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申请日2001-10-12
分类号A61K45/00;A61K31/404;A61P9/10;A61P25/00;A61P25/06;A61P25/08;A61P25/16;A61P25/28;A61P43/00;C07D209/34;G01N27/416;G01N33/15;G01N33/50;
国家 JP
入库时间 2022-08-21 23:26:48

Selective maxi-k potassium channel opener that functions under conditions of high intracellular calcium concentration, methods and uses

摘要

著录项

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