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

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

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20 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 language	English
Pages (from-to)	119-132
Number of pages	14
Journal	European Journal of Medicinal Chemistry
Volume	107
Early online date	2 Nov 2015
DOIs	https://doi.org/10.1016/j.ejmech.2015.10.050
Publication status	Published - 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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10.1016/j.ejmech.2015.10.050

Cite this

Yrjölä, S., Parkkari, T., Navia-Paldanius, D., Laitinen, T., Kaczor, A. A., Kokkola, T., Adusei-Mensah, F., Savinainen, J. R., Laitinen, J. T., Poso, A., Alexander, A., Penman, J., Stott, L., Anskat, M., Irving, A. J., & Nevalainen, T. J. (2016). Potent and selective N-(4-sulfamoylphenyl)thiourea-based GPR55 agonists. European Journal of Medicinal Chemistry, 107, 119-132. https://doi.org/10.1016/j.ejmech.2015.10.050

@article{b3b4c36a4aa447aa9c192e3f9311a2ec,

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.",

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",

author = "Sari Yrj{\"o}l{\"a} and Teija Parkkari and Dina Navia-Paldanius and Tuomo Laitinen and Kaczor, {Agnieszka A.} and Tarja Kokkola and Frank Adusei-Mensah and Savinainen, {Juha R.} and Laitinen, {Jarmo T.} and Antti Poso and Amy Alexander and June Penman and Lisa Stott and Marie Anskat and Irving, {Andrew J.} and Nevalainen, {Tapio J.}",

note = "This work was supported by the Academy of Finland (decision nos. 128056, 127653 and 139620), Biocenter Finland/DDCB, the National Graduate School of Organic Chemistry and Chemical Biology, and the Carnegie Trust (Scotland).",

year = "2016",

month = jan,

day = "1",

doi = "10.1016/j.ejmech.2015.10.050",

language = "English",

volume = "107",

pages = "119--132",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier",

}

Yrjölä, S, Parkkari, T, Navia-Paldanius, D, Laitinen, T, Kaczor, AA, Kokkola, T, Adusei-Mensah, F, Savinainen, JR, Laitinen, JT, Poso, A, Alexander, A, Penman, J, Stott, L, Anskat, M, Irving, AJ & Nevalainen, TJ 2016, 'Potent and selective N-(4-sulfamoylphenyl)thiourea-based GPR55 agonists', European Journal of Medicinal Chemistry, vol. 107, pp. 119-132. https://doi.org/10.1016/j.ejmech.2015.10.050

TY - JOUR

T1 - Potent and selective N-(4-sulfamoylphenyl)thiourea-based GPR55 agonists

AU - Yrjölä, Sari

AU - Parkkari, Teija

AU - Navia-Paldanius, Dina

AU - Laitinen, Tuomo

AU - Kaczor, Agnieszka A.

AU - Kokkola, Tarja

AU - Adusei-Mensah, Frank

AU - Savinainen, Juha R.

AU - Laitinen, Jarmo T.

AU - Poso, Antti

AU - Alexander, Amy

AU - Penman, June

AU - Stott, Lisa

AU - Anskat, Marie

AU - Irving, Andrew J.

AU - Nevalainen, Tapio J.

N1 - This work was supported by the Academy of Finland (decision nos. 128056, 127653 and 139620), Biocenter Finland/DDCB, the National Graduate School of Organic Chemistry and Chemical Biology, and the Carnegie Trust (Scotland).

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

KW - Cell line

KW - Chemistry techniques, Synthetic

KW - Drug design

KW - Drug evaluation, Preclinical

KW - Endocannabinoids

KW - Humans

KW - Ligands

KW - Models, Molecular

KW - Monoacylglycerol lipases

KW - Receptor, Cannabinoid, CB1

KW - Receptor, Cannabinoid, CB2

KW - Receptors, G-Protein-Coupled

KW - Structure-activity relationship

KW - Thiourea

KW - Journal article

KW - Research support, Non-U.S. Gov't

U2 - 10.1016/j.ejmech.2015.10.050

DO - 10.1016/j.ejmech.2015.10.050

M3 - Article

C2 - 26575458

SN - 0223-5234

VL - 107

SP - 119

EP - 132

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

Abstract

Keywords

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