On-target and off-target effects of novel orthosteric and allosteric activators of GPR84

Mancini, S., Mahmud, Z. A., Jenkins, L. , Bolognini, D., Newman, R., Barnes, M., Edye, M. E., McMahon, S. B., Tobin, A. B. and Milligan, G. (2019) On-target and off-target effects of novel orthosteric and allosteric activators of GPR84. Scientific Reports, 9, 1861. (doi: 10.1038/s41598-019-38539-1) (PMID:30755705) (PMCID:PMC6372602)

176543.pdf - Published Version
Available under License Creative Commons Attribution.



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.

Item Type:Articles
Additional Information:SM is funded by the Heptares Therapeutics sponsored Opportunities in Receptor Biology for Industrial Translation (ORBIT) scheme. ZAM thanks the Commonwealth Scholarship Commission for financial support.
Glasgow Author(s) Enlighten ID:Bolognini, Dr Daniele and Jenkins, Mrs Laura and Mancini, Dr Sarah and Milligan, Professor Graeme and Tobin, Andrew and Mahmud, Zobaer Al
Authors: Mancini, S., Mahmud, Z. A., Jenkins, L., Bolognini, D., Newman, R., Barnes, M., Edye, M. E., McMahon, S. B., Tobin, A. B., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Scientific Reports 9: 1861
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
659371Designer Receptor Exclusively Activated by Designer Drug' to define the role of short chain fatty acids in metabolic disease and inflammation (Fatty acid DREADD)Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/L027887/1RI MOLECULAR CELL & SYSTEMS BIOLOGY