Potent and selective N-(4-sulfamoylphenyl)thiourea-based GPR55 agonists

Sari Yrjölä; Teija Parkkari; Dina Navia-Paldanius; Tuomo Laitinen; Agnieszka A Kaczor; Tarja Kokkola; Frank Adusei-Mensah; Juha R Savinainen; Jarmo T Laitinen; Antti Poso; Amy Alexander; June Penman; Lisa Stott; Marie Anskat; Andrew J Irving; Tapio J Nevalainen

doi:10.1016/j.ejmech.2015.10.050

Potent and selective N-(4-sulfamoylphenyl)thiourea-based GPR55 agonists

Eur J Med Chem. 2016 Jan 1:107:119-32. doi: 10.1016/j.ejmech.2015.10.050. Epub 2015 Nov 2.

Authors

Sari Yrjölä¹, Teija Parkkari², Dina Navia-Paldanius³, Tuomo Laitinen⁴, Agnieszka A Kaczor⁵, Tarja Kokkola⁴, Frank Adusei-Mensah⁴, Juha R Savinainen³, Jarmo T Laitinen³, Antti Poso⁶, Amy Alexander⁷, June Penman⁷, Lisa Stott⁷, Marie Anskat⁷, Andrew J Irving⁸, Tapio J Nevalainen⁴

Affiliations

¹ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland. Electronic address: sari.yrjola@uef.fi.
² 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.
³ Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
⁴ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.
⁵ 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.
⁶ 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.
⁷ Division of Neuroscience, Medical Research Institute, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
⁸ 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.

PMID: 26575458
DOI: 10.1016/j.ejmech.2015.10.050

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.

Keywords: G protein-coupled receptor 55; Molecular modeling; Structure–activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Chemistry Techniques, Synthetic
Drug Design
Drug Evaluation, Preclinical / methods
Endocannabinoids / metabolism
Endocannabinoids / pharmacology
Humans
Ligands
Models, Molecular
Monoacylglycerol Lipases / metabolism
Receptor, Cannabinoid, CB1 / metabolism
Receptor, Cannabinoid, CB2 / metabolism
Receptors, Cannabinoid
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / metabolism
Structure-Activity Relationship*
Thiourea / chemistry*

Substances

Endocannabinoids
GPR55 protein, human
Ligands
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Receptors, Cannabinoid
Receptors, G-Protein-Coupled
ABHD12 protein, human
ABHD6 protein, human
Monoacylglycerol Lipases
Thiourea