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

• Published in: European journal of medicinal chemistry 2016-01, Vol.107, p.119-132
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Cell Line; Chemistry Techniques, Synthetic; Drug Design; Drug Evaluation, Preclinical - methods; Endocannabinoids - metabolism; Endocannabinoids - pharmacology; G protein-coupled receptor 55; Humans; Ligands; Models, Molecular; Molecular modeling; Monoacylglycerol Lipases - metabolism; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Structure-Activity Relationship; Structure–activity relationships; Thiourea - chemistry
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.10.050

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. [Display omitted] •We report the pharmacological evaluation of 27 GPR55 ligands.•Compounds have an N-(4-sulfamoylphenyl)thiourea scaffold.•N-aryl substituted sulfonamides proved to be the most potent GPR55 agonists.•Compounds were not active when tested against various endocannabinoid targets.