On-target and off-target effects of novel orthosteric and allosteric activators of GPR84
Many members of the G protein-coupled receptor family, including examples with clear therapeutic potential, remain poorly characterised. This often reflects limited availability of suitable tool ligands with which to interrogate receptor function. In the case of GPR84, currently a target for the treatment of idiopathic pulmonary fibrosis, recent times have seen the description of novel orthosteric and allosteric agonists. Using 2-(hexylthiol)pyrimidine-4,6 diol (2-HTP) and di(5,7-difluoro-1H-indole-3-yl)methane (PSB-16671) as exemplars of each class, in cell lines transfected to express either human or mouse GPR84, both ligands acted as effective on-target activators and with high co-operativity in their interactions. This was also the case in lipopolysaccharide-activated model human and mouse immune cell lines. However in mouse bone-marrow-derived neutrophils, where expression of GPR84 is particularly high, the capacity of PSB-16671 but not of 2-HTP to promote G protein activation was predominantly off-target because it was not blocked by an antagonist of GPR84 and was preserved in neutrophils isolated from GPR84 deficient mice. These results illustrate the challenges of attempting to study and define functions of poorly characterised receptors using ligands that have been developed via medicinal chemistry programmes, but where assessed activity has been limited largely to the initially identified target.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Scientific reports - 9(2019), 1 vom: 12. Feb., Seite 1861 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mancini, Sarah J [VerfasserIn] |
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| Links: |
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| Themen: |
EC 3.6.1.- |
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| Anmerkungen: |
Date Completed 23.09.2020 Date Revised 09.01.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-019-38539-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM293813922 |
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| 100 | 1 | |a Mancini, Sarah J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a On-target and off-target effects of novel orthosteric and allosteric activators of GPR84 |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Many members of the G protein-coupled receptor family, including examples with clear therapeutic potential, remain poorly characterised. This often reflects limited availability of suitable tool ligands with which to interrogate receptor function. In the case of GPR84, currently a target for the treatment of idiopathic pulmonary fibrosis, recent times have seen the description of novel orthosteric and allosteric agonists. Using 2-(hexylthiol)pyrimidine-4,6 diol (2-HTP) and di(5,7-difluoro-1H-indole-3-yl)methane (PSB-16671) as exemplars of each class, in cell lines transfected to express either human or mouse GPR84, both ligands acted as effective on-target activators and with high co-operativity in their interactions. This was also the case in lipopolysaccharide-activated model human and mouse immune cell lines. However in mouse bone-marrow-derived neutrophils, where expression of GPR84 is particularly high, the capacity of PSB-16671 but not of 2-HTP to promote G protein activation was predominantly off-target because it was not blocked by an antagonist of GPR84 and was preserved in neutrophils isolated from GPR84 deficient mice. These results illustrate the challenges of attempting to study and define functions of poorly characterised receptors using ligands that have been developed via medicinal chemistry programmes, but where assessed activity has been limited largely to the initially identified target | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a GPR84 protein, human |2 NLM | |
| 650 | 7 | |a Gpr84 protein, mouse |2 NLM | |
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| 700 | 1 | |a Mahmud, Zobaer Al |e verfasserin |4 aut | |
| 700 | 1 | |a Jenkins, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Bolognini, Daniele |e verfasserin |4 aut | |
| 700 | 1 | |a Newman, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Barnes, Matt |e verfasserin |4 aut | |
| 700 | 1 | |a Edye, Michelle E |e verfasserin |4 aut | |
| 700 | 1 | |a McMahon, Stephen B |e verfasserin |4 aut | |
| 700 | 1 | |a Tobin, Andrew B |e verfasserin |4 aut | |
| 700 | 1 | |a Milligan, Graeme |e verfasserin |4 aut | |
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