Are GPCRs still a source of new targets?
- PMID: 23945874
- DOI: 10.1177/1087057113498418
Are GPCRs still a source of new targets?
Abstract
G-protein-coupled receptors (GPCRs) still offer enormous scope for new therapeutic targets. Currently marketed agents are dominated by those with activity at aminergic receptors and yet they account for only ~10% of the family. Progress up until now with other subfamilies, notably orphans, Family A/peptide, Family A/lipid, Family B, Family C, and Family F, has been, at best, patchy. This may be attributable to the heterogeneous nature of GPCRs, their endogenous ligands, and consequently their binding sites. Our appreciation of receptor similarity has arguably been too simplistic, and screening collections have not necessarily been well suited to identifying leads in new areas. Despite the relative shortage of high-quality tool molecules in a number of cases, there is an emerging, and increasingly substantial, body of evidence associating many as yet "undrugged" receptors with a very wide range of diseases. Significant advances in our understanding of receptor pharmacology and technical advances in screening, protein X-ray crystallography, and ligand design methods are paving the way for new successes in the area. Exploitation of allosteric mechanisms; alternative signaling pathways such as G12/13, Gβγ, and β-arrestin; the discovery of "biased" ligands; and the emergence of GPCR-protein complexes as potential drug targets offer scope for new and much improved drugs.
Keywords: chemogenomics; functional selectivity; lead discovery; review.
Similar articles
-
GPCR structures in drug design, emerging opportunities with new structures.Bioorg Med Chem Lett. 2014 Sep 1;24(17):4073-9. doi: 10.1016/j.bmcl.2014.07.009. Epub 2014 Jul 10. Bioorg Med Chem Lett. 2014. PMID: 25086683 Review.
-
Emerging opportunities for allosteric modulation of G-protein coupled receptors.Biochem Pharmacol. 2013 Jan 15;85(2):153-62. doi: 10.1016/j.bcp.2012.09.001. Epub 2012 Sep 11. Biochem Pharmacol. 2013. PMID: 22975406 Review.
-
Allosteric ligands for G protein-coupled receptors: a novel strategy with attractive therapeutic opportunities.Med Res Rev. 2010 May;30(3):463-549. doi: 10.1002/med.20166. Med Res Rev. 2010. PMID: 19557759 Review.
-
[G-protein-coupled receptors plasticity and signalling].Med Sci (Paris). 2012 Oct;28(10):883-5. doi: 10.1051/medsci/20122810018. Epub 2012 Oct 12. Med Sci (Paris). 2012. PMID: 23067421 Review. French.
-
A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design.Br J Pharmacol. 2013 Sep;170(1):101-26. doi: 10.1111/bph.12248. Br J Pharmacol. 2013. PMID: 23713847 Free PMC article.
Cited by
-
G-Protein-Coupled Receptor 35 Mediates Human Saphenous Vein Vascular Smooth Muscle Cell Migration and Endothelial Cell Proliferation.J Vasc Res. 2015;52(6):383-95. doi: 10.1159/000444754. Epub 2016 Apr 12. J Vasc Res. 2015. PMID: 27064272 Free PMC article.
-
G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease.Front Pharmacol. 2015 Mar 10;6:41. doi: 10.3389/fphar.2015.00041. eCollection 2015. Front Pharmacol. 2015. PMID: 25805994 Free PMC article. Review.
-
Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1.Nat Commun. 2023 Dec 9;14(1):8155. doi: 10.1038/s41467-023-44010-7. Nat Commun. 2023. PMID: 38071229 Free PMC article.
-
Identification and expression profiles of neuropeptides and their G protein-coupled receptors in the rice stem borer Chilo suppressalis.Sci Rep. 2016 Jun 29;6:28976. doi: 10.1038/srep28976. Sci Rep. 2016. PMID: 27353701 Free PMC article.
-
Superagonism at G protein-coupled receptors and beyond.Br J Pharmacol. 2016 Oct;173(20):3018-27. doi: 10.1111/bph.13278. Epub 2015 Oct 24. Br J Pharmacol. 2016. PMID: 26276510 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources