Loading…

Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy

The lipid-activated G protein-coupled receptor (GPCR) GPR55 has been proposed as a drug target for the treatment of chronic diseases including inflammation, neurodegeneration, neuropathic pain, metabolic diseases, and cancer. A series of chromen-4-one-2-carboxylic acid derivatives was synthesized wi...

Full description

Saved in:
Bibliographic Details
Published in:ACS omega 2019-02, Vol.4 (2), p.4276-4295
Main Authors: Schoeder, Clara T, Meyer, Anne, Mahardhika, Andhika B, Thimm, Dominik, Blaschke, Thomas, Funke, Mario, Müller, Christa E
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-a388t-1fd08c671908ef7867f197fe19cc491b1a119dd4b8a3d866f124e4b31a67211c3
cites cdi_FETCH-LOGICAL-a388t-1fd08c671908ef7867f197fe19cc491b1a119dd4b8a3d866f124e4b31a67211c3
container_end_page 4295
container_issue 2
container_start_page 4276
container_title ACS omega
container_volume 4
creator Schoeder, Clara T
Meyer, Anne
Mahardhika, Andhika B
Thimm, Dominik
Blaschke, Thomas
Funke, Mario
Müller, Christa E
description The lipid-activated G protein-coupled receptor (GPCR) GPR55 has been proposed as a drug target for the treatment of chronic diseases including inflammation, neurodegeneration, neuropathic pain, metabolic diseases, and cancer. A series of chromen-4-one-2-carboxylic acid derivatives was synthesized with the aim to obtain potent and selective ligands for GPR55 by (i) attachment of a variety of substituted 8-benzamido residues, (ii) substitution in position 6 by halogen atoms, and (iii) thioation of the 4-oxo function. The compounds were investigated in β-arrestin recruitment assays using enzyme complementation. Depending on the substitution pattern, a spectrum of efficacies was obtained ranging from (partial) agonists to antagonists. 6-Chloro-8-(3-((5-cyclohexylpentyl)­oxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (74, PSB-18251) displayed the highest efficacy of the series combined with high potency (EC50 0.196 μM). 6-Chloro-8-(3-(heptyloxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (76, PSB-18337) exhibited higher potency (EC50 0.0400 μM) but lower efficacy (39%). Several GPR55 antagonists were discovered including 8-(3-(cyclohexylmethoxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (57, PSB-18263) (IC50 8.23 μM) and 4-oxo-8-(3-phenethoxybenzamido)-4H-chromene-2-carboxylic acid (65, PSB-18270) (IC50 3.96 μM). These potent GPR55 agonists and antagonists showed high selectivity versus the related GPCRs GPR18 and GPR35 tested in the same assay system, while 8-(4-(4-cyclohexylbutoxy)­benzamido)-6-fluoro-4-oxo-4H-chromene-2-carboxylic acid (84, PSB-18177) represents a dual GPR35/GPR55 antagonist (IC50 GPR55: 3.26 μM, GPR35: 2.57 μM). Binding studies of selected compounds at CB1 and CB2 receptors indicated GPR55 selectivity also versus CB receptors. The newly developed GPR55 (partial) agonists and antagonists will be useful tools for evaluating the suitability of GPR55 as a drug target.
doi_str_mv 10.1021/acsomega.8b03695
format article
fullrecord <record><control><sourceid>acs_doaj_</sourceid><recordid>TN_cdi_doaj_primary_oai_doaj_org_article_4c331554a18845e7ac2cfd036a611368</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_4c331554a18845e7ac2cfd036a611368</doaj_id><sourcerecordid>b113948153</sourcerecordid><originalsourceid>FETCH-LOGICAL-a388t-1fd08c671908ef7867f197fe19cc491b1a119dd4b8a3d866f124e4b31a67211c3</originalsourceid><addsrcrecordid>eNp1kUFr3DAQhU1ooSHNvUcdU6hTjSXL8nHZpJvAQkNIz2Isj3a1eC0jabfkH_Rnx-mmpZeeZph57xuGVxSfgF8Dr-Ar2hT2tMFr3XGh2vqsOK9kw0sQUrz7p_9QXKa045yD0pWu1Hnx64aONIRpT2NmwbHlNs6ksZRlGIndUPRHzP5IiWFiV4sxf8ZNGH3KibkQWd4SW_vJ9-XC5lcp9WzFHmLI5MdyGQ7TME8eydKUZ_nq4bGu2U-ft-zpMGI3ELt1zlu0zx-L9w6HRJdv9aL48e32aXlXrr-v7peLdYlC61yC67m2qoGWa3KNVo2DtnEErbWyhQ4QoO172WkUvVbKQSVJdgJQNRWAFRfF_YnbB9yZKfo9xmcT0JvfgxA3BmP2diAjrRBQ1xJBa1lTg7ay83mhUAEIpWcWP7FsDClFcn95wM1rMOZPMOYtmNny5WSZN2YXDnGcn_2__AU3opE-</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy</title><source>NCBI_PubMed Central(免费)</source><source>American Chemical Society (ACS) Open Access</source><creator>Schoeder, Clara T ; Meyer, Anne ; Mahardhika, Andhika B ; Thimm, Dominik ; Blaschke, Thomas ; Funke, Mario ; Müller, Christa E</creator><creatorcontrib>Schoeder, Clara T ; Meyer, Anne ; Mahardhika, Andhika B ; Thimm, Dominik ; Blaschke, Thomas ; Funke, Mario ; Müller, Christa E</creatorcontrib><description>The lipid-activated G protein-coupled receptor (GPCR) GPR55 has been proposed as a drug target for the treatment of chronic diseases including inflammation, neurodegeneration, neuropathic pain, metabolic diseases, and cancer. A series of chromen-4-one-2-carboxylic acid derivatives was synthesized with the aim to obtain potent and selective ligands for GPR55 by (i) attachment of a variety of substituted 8-benzamido residues, (ii) substitution in position 6 by halogen atoms, and (iii) thioation of the 4-oxo function. The compounds were investigated in β-arrestin recruitment assays using enzyme complementation. Depending on the substitution pattern, a spectrum of efficacies was obtained ranging from (partial) agonists to antagonists. 6-Chloro-8-(3-((5-cyclohexylpentyl)­oxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (74, PSB-18251) displayed the highest efficacy of the series combined with high potency (EC50 0.196 μM). 6-Chloro-8-(3-(heptyloxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (76, PSB-18337) exhibited higher potency (EC50 0.0400 μM) but lower efficacy (39%). Several GPR55 antagonists were discovered including 8-(3-(cyclohexylmethoxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (57, PSB-18263) (IC50 8.23 μM) and 4-oxo-8-(3-phenethoxybenzamido)-4H-chromene-2-carboxylic acid (65, PSB-18270) (IC50 3.96 μM). These potent GPR55 agonists and antagonists showed high selectivity versus the related GPCRs GPR18 and GPR35 tested in the same assay system, while 8-(4-(4-cyclohexylbutoxy)­benzamido)-6-fluoro-4-oxo-4H-chromene-2-carboxylic acid (84, PSB-18177) represents a dual GPR35/GPR55 antagonist (IC50 GPR55: 3.26 μM, GPR35: 2.57 μM). Binding studies of selected compounds at CB1 and CB2 receptors indicated GPR55 selectivity also versus CB receptors. The newly developed GPR55 (partial) agonists and antagonists will be useful tools for evaluating the suitability of GPR55 as a drug target.</description><identifier>ISSN: 2470-1343</identifier><identifier>EISSN: 2470-1343</identifier><identifier>DOI: 10.1021/acsomega.8b03695</identifier><language>eng</language><publisher>American Chemical Society</publisher><ispartof>ACS omega, 2019-02, Vol.4 (2), p.4276-4295</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a388t-1fd08c671908ef7867f197fe19cc491b1a119dd4b8a3d866f124e4b31a67211c3</citedby><cites>FETCH-LOGICAL-a388t-1fd08c671908ef7867f197fe19cc491b1a119dd4b8a3d866f124e4b31a67211c3</cites><orcidid>0000-0002-0013-6624</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acsomega.8b03695$$EPDF$$P50$$Gacs$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acsomega.8b03695$$EHTML$$P50$$Gacs$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,27078,27922,27923,56760,56810</link.rule.ids></links><search><creatorcontrib>Schoeder, Clara T</creatorcontrib><creatorcontrib>Meyer, Anne</creatorcontrib><creatorcontrib>Mahardhika, Andhika B</creatorcontrib><creatorcontrib>Thimm, Dominik</creatorcontrib><creatorcontrib>Blaschke, Thomas</creatorcontrib><creatorcontrib>Funke, Mario</creatorcontrib><creatorcontrib>Müller, Christa E</creatorcontrib><title>Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy</title><title>ACS omega</title><addtitle>ACS Omega</addtitle><description>The lipid-activated G protein-coupled receptor (GPCR) GPR55 has been proposed as a drug target for the treatment of chronic diseases including inflammation, neurodegeneration, neuropathic pain, metabolic diseases, and cancer. A series of chromen-4-one-2-carboxylic acid derivatives was synthesized with the aim to obtain potent and selective ligands for GPR55 by (i) attachment of a variety of substituted 8-benzamido residues, (ii) substitution in position 6 by halogen atoms, and (iii) thioation of the 4-oxo function. The compounds were investigated in β-arrestin recruitment assays using enzyme complementation. Depending on the substitution pattern, a spectrum of efficacies was obtained ranging from (partial) agonists to antagonists. 6-Chloro-8-(3-((5-cyclohexylpentyl)­oxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (74, PSB-18251) displayed the highest efficacy of the series combined with high potency (EC50 0.196 μM). 6-Chloro-8-(3-(heptyloxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (76, PSB-18337) exhibited higher potency (EC50 0.0400 μM) but lower efficacy (39%). Several GPR55 antagonists were discovered including 8-(3-(cyclohexylmethoxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (57, PSB-18263) (IC50 8.23 μM) and 4-oxo-8-(3-phenethoxybenzamido)-4H-chromene-2-carboxylic acid (65, PSB-18270) (IC50 3.96 μM). These potent GPR55 agonists and antagonists showed high selectivity versus the related GPCRs GPR18 and GPR35 tested in the same assay system, while 8-(4-(4-cyclohexylbutoxy)­benzamido)-6-fluoro-4-oxo-4H-chromene-2-carboxylic acid (84, PSB-18177) represents a dual GPR35/GPR55 antagonist (IC50 GPR55: 3.26 μM, GPR35: 2.57 μM). Binding studies of selected compounds at CB1 and CB2 receptors indicated GPR55 selectivity also versus CB receptors. The newly developed GPR55 (partial) agonists and antagonists will be useful tools for evaluating the suitability of GPR55 as a drug target.</description><issn>2470-1343</issn><issn>2470-1343</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>DOA</sourceid><recordid>eNp1kUFr3DAQhU1ooSHNvUcdU6hTjSXL8nHZpJvAQkNIz2Isj3a1eC0jabfkH_Rnx-mmpZeeZph57xuGVxSfgF8Dr-Ar2hT2tMFr3XGh2vqsOK9kw0sQUrz7p_9QXKa045yD0pWu1Hnx64aONIRpT2NmwbHlNs6ksZRlGIndUPRHzP5IiWFiV4sxf8ZNGH3KibkQWd4SW_vJ9-XC5lcp9WzFHmLI5MdyGQ7TME8eydKUZ_nq4bGu2U-ft-zpMGI3ELt1zlu0zx-L9w6HRJdv9aL48e32aXlXrr-v7peLdYlC61yC67m2qoGWa3KNVo2DtnEErbWyhQ4QoO172WkUvVbKQSVJdgJQNRWAFRfF_YnbB9yZKfo9xmcT0JvfgxA3BmP2diAjrRBQ1xJBa1lTg7ay83mhUAEIpWcWP7FsDClFcn95wM1rMOZPMOYtmNny5WSZN2YXDnGcn_2__AU3opE-</recordid><startdate>20190228</startdate><enddate>20190228</enddate><creator>Schoeder, Clara T</creator><creator>Meyer, Anne</creator><creator>Mahardhika, Andhika B</creator><creator>Thimm, Dominik</creator><creator>Blaschke, Thomas</creator><creator>Funke, Mario</creator><creator>Müller, Christa E</creator><general>American Chemical Society</general><scope>N~.</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-0013-6624</orcidid></search><sort><creationdate>20190228</creationdate><title>Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy</title><author>Schoeder, Clara T ; Meyer, Anne ; Mahardhika, Andhika B ; Thimm, Dominik ; Blaschke, Thomas ; Funke, Mario ; Müller, Christa E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a388t-1fd08c671908ef7867f197fe19cc491b1a119dd4b8a3d866f124e4b31a67211c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schoeder, Clara T</creatorcontrib><creatorcontrib>Meyer, Anne</creatorcontrib><creatorcontrib>Mahardhika, Andhika B</creatorcontrib><creatorcontrib>Thimm, Dominik</creatorcontrib><creatorcontrib>Blaschke, Thomas</creatorcontrib><creatorcontrib>Funke, Mario</creatorcontrib><creatorcontrib>Müller, Christa E</creatorcontrib><collection>American Chemical Society (ACS) Open Access</collection><collection>CrossRef</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>ACS omega</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schoeder, Clara T</au><au>Meyer, Anne</au><au>Mahardhika, Andhika B</au><au>Thimm, Dominik</au><au>Blaschke, Thomas</au><au>Funke, Mario</au><au>Müller, Christa E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy</atitle><jtitle>ACS omega</jtitle><addtitle>ACS Omega</addtitle><date>2019-02-28</date><risdate>2019</risdate><volume>4</volume><issue>2</issue><spage>4276</spage><epage>4295</epage><pages>4276-4295</pages><issn>2470-1343</issn><eissn>2470-1343</eissn><abstract>The lipid-activated G protein-coupled receptor (GPCR) GPR55 has been proposed as a drug target for the treatment of chronic diseases including inflammation, neurodegeneration, neuropathic pain, metabolic diseases, and cancer. A series of chromen-4-one-2-carboxylic acid derivatives was synthesized with the aim to obtain potent and selective ligands for GPR55 by (i) attachment of a variety of substituted 8-benzamido residues, (ii) substitution in position 6 by halogen atoms, and (iii) thioation of the 4-oxo function. The compounds were investigated in β-arrestin recruitment assays using enzyme complementation. Depending on the substitution pattern, a spectrum of efficacies was obtained ranging from (partial) agonists to antagonists. 6-Chloro-8-(3-((5-cyclohexylpentyl)­oxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (74, PSB-18251) displayed the highest efficacy of the series combined with high potency (EC50 0.196 μM). 6-Chloro-8-(3-(heptyloxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (76, PSB-18337) exhibited higher potency (EC50 0.0400 μM) but lower efficacy (39%). Several GPR55 antagonists were discovered including 8-(3-(cyclohexylmethoxy)­benzamido)-4-oxo-4H-chromene-2-carboxylic acid (57, PSB-18263) (IC50 8.23 μM) and 4-oxo-8-(3-phenethoxybenzamido)-4H-chromene-2-carboxylic acid (65, PSB-18270) (IC50 3.96 μM). These potent GPR55 agonists and antagonists showed high selectivity versus the related GPCRs GPR18 and GPR35 tested in the same assay system, while 8-(4-(4-cyclohexylbutoxy)­benzamido)-6-fluoro-4-oxo-4H-chromene-2-carboxylic acid (84, PSB-18177) represents a dual GPR35/GPR55 antagonist (IC50 GPR55: 3.26 μM, GPR35: 2.57 μM). Binding studies of selected compounds at CB1 and CB2 receptors indicated GPR55 selectivity also versus CB receptors. The newly developed GPR55 (partial) agonists and antagonists will be useful tools for evaluating the suitability of GPR55 as a drug target.</abstract><pub>American Chemical Society</pub><doi>10.1021/acsomega.8b03695</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0002-0013-6624</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2470-1343
ispartof ACS omega, 2019-02, Vol.4 (2), p.4276-4295
issn 2470-1343
2470-1343
language eng
recordid cdi_doaj_primary_oai_doaj_org_article_4c331554a18845e7ac2cfd036a611368
source NCBI_PubMed Central(免费); American Chemical Society (ACS) Open Access
title Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T13%3A32%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-acs_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Development%20of%20Chromen-4-one%20Derivatives%20as%20(Ant)agonists%20for%20the%20Lipid-Activated%20G%20Protein-Coupled%20Receptor%20GPR55%20with%20Tunable%20Efficacy&rft.jtitle=ACS%20omega&rft.au=Schoeder,%20Clara%20T&rft.date=2019-02-28&rft.volume=4&rft.issue=2&rft.spage=4276&rft.epage=4295&rft.pages=4276-4295&rft.issn=2470-1343&rft.eissn=2470-1343&rft_id=info:doi/10.1021/acsomega.8b03695&rft_dat=%3Cacs_doaj_%3Eb113948153%3C/acs_doaj_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-a388t-1fd08c671908ef7867f197fe19cc491b1a119dd4b8a3d866f124e4b31a67211c3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true