Yrjölä Sari, Parkkari Teija, Navia-Paldanius Dina, Laitinen Tuomo, Kaczor Agnieszka A, Kokkola Tarja, Adusei-Mensah Frank, Savinainen Juha R, Laitinen Jarmo T, Poso Antti, Alexander Amy, Penman June, Stott Lisa, Anskat Marie, Irving Andrew J, Nevalainen Tapio J
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland; Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
Eur J Med Chem. 2016 Jan 1;107:119-32. doi: 10.1016/j.ejmech.2015.10.050. Epub 2015 Nov 2.
To date, many known G protein-coupled receptor 55 (GPR55) ligands are those identified among the cannabinoids. In order to further study the function of GPR55, new potent and selective ligands are needed. In this study, we utilized the screening results from PubChem bioassay AID 1961 which reports the results of Image-based HTS for Selective Agonists of GPR55. Three compounds, CID1792579, CID1252842 and CID1011163, were further evaluated and used as a starting point to create a series of nanomolar potency GPR55 agonists with N-(4-sulfamoylphenyl)thiourea scaffold. The GPR55 activity of the compounds were screened by using a commercial β-arrestin PathHunter assay and the potential compounds were further evaluated by using a recombinant HEK cell line exhibiting GPR55-mediated effects on calcium signalling. The designed compounds were not active when tested against various endocannabinoid targets (CB1R, CB2R, FAAH, MGL, ABHD6 and ABHD12), indicating compounds' selectivity for the GPR55. Finally, structure-activity relationships of these compounds were explored.
迄今为止，许多已知的G蛋白偶联受体55（GPR55）配体是在大麻素中鉴定出来的。为了进一步研究GPR55的功能，需要新的强效和选择性配体。在本研究中，我们利用了PubChem生物测定AID 1961的筛选结果，该结果报告了基于图像的GPR55选择性激动剂的高通量筛选结果。对三种化合物CID1792579、CID1252842和CID1011163进行了进一步评估，并以此为起点，创建了一系列具有N-（4-氨磺酰基苯基）硫脲支架的纳摩尔效价GPR55激动剂。通过使用商业β-抑制蛋白PathHunter测定法筛选化合物的GPR55活性，并使用表现出GPR55介导的钙信号传导作用的重组HEK细胞系对潜在化合物进行进一步评估。当针对各种内源性大麻素靶点（CB1R、CB2R、FAAH、MGL、ABHD6和ABHD12）进行测试时，设计的化合物没有活性，表明化合物对GPR55具有选择性。最后，探索了这些化合物的构效关系。
