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

Sari Yrjölä (Lead / Corresponding author), 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

    Research output: Contribution to journalArticlepeer-review

    14 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)119-132
    Number of pages14
    JournalEuropean Journal of Medicinal Chemistry
    Volume107
    Early online date2 Nov 2015
    DOIs
    Publication statusPublished - 1 Jan 2016

    Keywords

    • Cell line
    • Chemistry techniques, Synthetic
    • Drug design
    • Drug evaluation, Preclinical
    • Endocannabinoids
    • Humans
    • Ligands
    • Models, Molecular
    • Monoacylglycerol lipases
    • Receptor, Cannabinoid, CB1
    • Receptor, Cannabinoid, CB2
    • Receptors, G-Protein-Coupled
    • Structure-activity relationship
    • Thiourea
    • Journal article
    • Research support, Non-U.S. Gov't

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