title: Potent and selective N-(4-sulfamoylphenyl)thiourea-based GPR55 agonists.
abstract: 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.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland. Electronic address: sari.yrjola@uef.fi.
authors.forename: Sari
authors.initials: S
authors.lastname: Yrjölä
authors.affiliation: 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.
authors.forename: Teija
authors.initials: T
authors.lastname: Parkkari
authors.affiliation: Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Dina
authors.initials: D
authors.lastname: Navia-Paldanius
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland; Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Kokkola
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Frank
authors.initials: F
authors.lastname: Adusei-Mensah
authors.affiliation: Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Juha R
authors.initials: JR
authors.lastname: Savinainen
authors.affiliation: Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Jarmo T
authors.initials: JT
authors.lastname: Laitinen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland; Division of Translational Gastrointestinal Oncology, Dept. of Internal Medicine I, University Hospital Tübingen, Otfried-Mueller-Strasse 10, 72076 Tübingen, Germany.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: June
authors.initials: J
authors.lastname: Penman
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stott
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Anskat
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK; School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin D4, Ireland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Irving
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Tapio J
authors.initials: TJ
authors.lastname: Nevalainen
mesh_terms: D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D063388:Endocannabinoids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry*
chemical_list: D063388:Endocannabinoids; C524885:GPR55 protein, human; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; C552558:ABHD12 protein, human; C540878:ABHD6 protein, human; D008994:Monoacylglycerol Lipases; D013890:Thiourea
keywords: G protein-coupled receptor 55; Molecular modeling; Structure–activity relationships