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Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system.靶向中枢神经系统中G蛋白门控内向整流钾通道（GIRK通道）的治疗潜力
Pharmacol Ther. 2021 Jul;223:107808. doi: 10.1016/j.pharmthera.2021.107808. Epub 2021 Jan 18.
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Advances in Targeting GIRK Channels in Disease.疾病中靶向 GIRK 通道的研究进展。
Trends Pharmacol Sci. 2021 Mar;42(3):203-215. doi: 10.1016/j.tips.2020.12.002. Epub 2021 Jan 16.
3
Antinociceptive effect of selective G protein-gated inwardly rectifying K+ channel agonist ML297 in the rat spinal cord.选择性 G 蛋白门控内向整流钾通道激动剂 ML297 在大鼠脊髓中的抗伤害作用。
PLoS One. 2020 Sep 11;15(9):e0239094. doi: 10.1371/journal.pone.0239094. eCollection 2020.
4
The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents.小分子 GAT1508 激活大脑特异性 GIRK1/2 通道异源二聚体，并促进啮齿动物条件性恐惧的消退。
J Biol Chem. 2020 Mar 13;295(11):3614-3634. doi: 10.1074/jbc.RA119.011527. Epub 2020 Jan 17.
5
Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators.发现、合成及表征一系列（1-烷基-3-甲基-1H-吡唑-5-基）-2-（5-芳基-2H-四唑-2-基）乙酰胺作为新型 GIRK1/2 钾通道激活剂。
Bioorg Med Chem Lett. 2019 Mar 15;29(6):791-796. doi: 10.1016/j.bmcl.2019.01.027. Epub 2019 Jan 23.
6
Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models.单独使用和与吗啡联合使用 GIRK 激活剂 VU0466551 在急性和持续性疼痛模型中的镇痛效果。
ACS Chem Neurosci. 2019 Mar 20;10(3):1294-1299. doi: 10.1021/acschemneuro.8b00370. Epub 2018 Dec 11.
7
Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators.发现并描述 1H-吡唑-5-基-2-苯基乙酰胺作为新型非脲基含有的 GIRK1/2 钾通道激活剂。
ACS Chem Neurosci. 2017 Sep 20;8(9):1873-1879. doi: 10.1021/acschemneuro.7b00217. Epub 2017 Jul 19.
8
G Protein-Gated Potassium Channels: A Link to Drug Addiction.G蛋白门控钾通道：与药物成瘾的联系。
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GIRK Channel Plasticity and Implications for Drug Addiction.GIRK通道可塑性及其对药物成瘾的影响。
Int Rev Neurobiol. 2015;123:201-38. doi: 10.1016/bs.irn.2015.05.011. Epub 2015 Jun 22.
10
G protein-gated inwardly rectifying potassium channel subunits 1 and 2 are down-regulated in rat dorsal root ganglion neurons and spinal cord after peripheral axotomy.外周轴突切断后，大鼠背根神经节神经元和脊髓中的G蛋白门控内向整流钾通道亚基1和2表达下调。
Mol Pain. 2015 Jul 22;11:44. doi: 10.1186/s12990-015-0044-z.

一系列新型GIRK1/2钾通道激活剂——α-(1-(1,1-二氧代四氢噻吩-3-基)-3-甲基-1-吡唑-5-基)乙酰胺醚的发现、合成及生物学特性研究

Discovery, synthesis and biological characterization of a series of -(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1-pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators.

作者信息

Sharma Swagat, Lesiak Lauren, Aretz Christopher D, Du Yu, Kumar Sushil, Gautam Nagsen, Alnouti Yazen, Dhuria Nikilesh V, Chhonker Yashpal S, Weaver C David, Hopkins Corey R

机构信息

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha NE 68198 USA

Department of Pharmacology, Vanderbilt University School of Medicine Nashville TN 37232 USA.

出版信息

RSC Med Chem. 2021 Jun 21;12(8):1366-1373. doi: 10.1039/d1md00129a. eCollection 2021 Aug 18.

DOI:10.1039/d1md00129a
PMID:34458739
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8372201/
Abstract

The present study describes the discovery and characterization of a series of -(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1-pyrazol-5-yl)acetamide ethers as G protein-gated inwardly-rectifying potassium (GIRK) channel activators. From our previous lead optimization efforts, we have identified a new ether-based scaffold and paired this with a novel sulfone-based head group to identify a potent and selective GIRK1/2 activator. In addition, we evaluated the compounds in tier 1 DMPK assays and have identified compounds that display nanomolar potency as GIRK1/2 activators with improved metabolic stability over the prototypical urea-based compounds.

摘要

本研究描述了一系列-(1-(1,1-二氧代四氢噻吩-3-基)-3-甲基-1-吡唑-5-基)乙酰胺醚作为G蛋白门控内向整流钾通道（GIRK）激活剂的发现和特性。通过我们之前的先导化合物优化工作，我们确定了一种新的基于醚的骨架，并将其与一种新型的基于砜的头部基团配对，以鉴定出一种强效且选择性的GIRK1/2激活剂。此外，我们在一级DMPK分析中评估了这些化合物，并确定了作为GIRK1/2激活剂具有纳摩尔效力且代谢稳定性优于原型脲基化合物的化合物。