G protein-coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35.
G protein-coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35.
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DOI：
10.1111/bph.14042
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发表时间：
2018-07
影响因子：
7.3
通讯作者：
Milligan G
中科院分区：
文献类型：
--
作者：
Milligan G
人们普遍认为，G蛋白偶联受体是开发小分子药物最成功的一类靶标。尽管如此，迄今为止，人类基因组中不到15%的非嗅觉G蛋白偶联受体是临床使用药物的靶点。在许多情况下，这可能反映了对许多G蛋白偶联受体的基础生物学缺乏了解，这些受体目前尚未受到关注，以及缺乏药理学工具化合物和适当的动物模型来测试这些G蛋白偶联受体在正常生理学和疾病背景下的体内功能。“开放式创新”安排，其中制药公司和公私伙伴关系提供更广泛的获得从配体筛选方案中确定的工具化合物的机会，同时加强药物化学支持，将这种筛选“命中”转化为有用的“工具”化合物，将提供重要的途径，以提高认识。然而，与此同时，定义和充分理解这些工具化合物的选择性和作用模式的新方法，以及更好地理解目前广泛的了解不足和研究不足的G蛋白偶联受体的药理学和/或信号传导谱中的潜在物种直向同源物变异性，对于充分利用这一大型靶类的治疗潜力至关重要。我认为这些主题使用两个G蛋白偶联受体作为例子，游离脂肪酸受体2和GPR 35。
It is widely appreciated that G protein‐coupled receptors have been the most successfully exploited class of targets for the development of small molecule medicines. Despite this, to date, less than 15% of the non‐olfactory G protein‐coupled receptors in the human genome are the targets of a clinically used medicine. In many cases, this is likely to reflect a lack of understanding of the basic underpinning biology of many G protein‐coupled receptors that are not currently in the spotlight, as well as a paucity of pharmacological tool compounds and appropriate animal models to test in vivo function of such G protein‐coupled receptors in both normal physiology and in the context of disease. ‘Open Innovation’ arrangements, in which pharmaceutical companies and public–private partnerships provide wider access to tool compounds identified from ligand screening programmes, alongside enhanced medicinal chemistry support to convert such screening ‘hits’ into useful ‘tool’ compounds will provide important routes to improved understanding. However, in parallel, novel approaches to define and fully appreciate the selectivity and mode of action of such tool compounds, as well as better understanding of potential species orthologue variability in the pharmacology and/or signalling profile of a wide range of currently poorly understood and understudied G protein‐coupled receptors, will be vital to fully exploit the therapeutic potential of this large target class. I consider these themes using as exemplars two G protein‐coupled receptors, free fatty acid receptor 2 and GPR35.
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DOI：
10.1096/fj.12-213314
发表时间：
2012-12
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Hudson BD;Christiansen E;Tikhonova IG;Grundmann M;Kostenis E;Adams DR;Ulven T;Milligan G
通讯作者：
Milligan G
DOI：
10.1152/ajpendo.00229.2010
发表时间：
2011-01-01
影响因子：
5.1
作者：
Bjursell, Mikael;Admyre, Therese;Bohlooly-Y, Mohammad
通讯作者：
Bohlooly-Y, Mohammad
影响因子：
5.6
作者：
Divorty N;Mackenzie AE;Nicklin SA;Milligan G
通讯作者：
Milligan G
影响因子：
4.8
作者：
Brown, AJ;Goldsworthy, SM;Dowell, SJ
通讯作者：
Dowell, SJ
影响因子：
5.8
作者：
Alkondon, Manickavasagom;Pereira, Edna F. R.;Albuquerque, Edson X.
通讯作者：
Albuquerque, Edson X.