Days Emily, Kaufmann Kristian, Romaine Ian, Niswender Colleen, Lewis Michelle, Utley Thomas, Du Yu, Sliwoski Gregory, Morrison Ryan, Dawson Eric S., Engers Julie L., Denton Jerod, Daniels J. Scott, Sulikowski Gary A., Lindsley Craig W., Weaver C. David
We have developed the first potent, subtype-selective small molecule activator of a G-protein activated inward-rectifying potassium (GIRK) channel. ML297 is potent (EC = 160 nM) and as efficacious as activation of GIRK via a G-coupled receptor (GPCR). ML297 shows a preference for the GIRK1/GIRK2 subunit combination compared to GIRK1/GIRK4 and is inactive on GIRK2/GIRK3 and a number of other potassium channels. This represents a major advance in this field, as the only other known small molecule activators of GIRK channels are simple alcohols and the natural product, naringin, all of which are very low potency and non-selective with respect to GIRK subtype. ML297 possesses favorable physiochemical and dystrophia myotonica protein kinase (DMPK) properties (ML297 is centrally penetrant, affording good CNS exposure in rats), making it a useful tool to selectively probe GIRK1-containing GIRK function and which will allow the role of GIRK1-containing GIRKs to be studied in numerous normal and pathophysiological conditions. These properties make ML297 the first and only molecule of its type to selectively probe GIRK1-containing GIRKs and will for the first time allow the potential therapeutic utility of GIRK as a target for numerous important therapeutic indications to be examined.
我们研发出了首个强效、亚型选择性的G蛋白激活内向整流钾通道（GIRK）小分子激活剂。ML297效力强大（EC = 160 nM），其激活GIRK的效果与通过G偶联受体（GPCR）激活GIRK相当。与GIRK1/GIRK4相比，ML297对GIRK1/GIRK2亚基组合表现出偏好，对GIRK2/GIRK3及其他多种钾通道无活性。这代表了该领域的一项重大进展，因为此前已知的仅有的其他GIRK通道小分子激活剂是简单醇类和天然产物柚皮苷，所有这些激活剂效力都非常低，且对GIRK亚型无选择性。ML297具有良好的物理化学性质和强直性肌营养不良蛋白激酶（DMPK）特性（ML297能穿透血脑屏障，在大鼠体内能实现良好的中枢神经系统暴露），使其成为选择性探究含GIRK1的GIRK功能的有用工具，这将有助于在众多正常和病理生理条件下研究含GIRK1的GIRK的作用。这些特性使ML297成为首个也是唯一能选择性探究含GIRK1的GIRK的此类分子，并将首次使得能够研究GIRK作为众多重要治疗适应症靶点的潜在治疗效用。
