Trends in GPCR Drug Discovery: New Agents, Targets and Indications

Overview

Journal Nat Rev Drug Discov

Specialty Pharmacology

Date 2017 Oct 28

PMID 29075003

Citations 1065

Authors

Alexander S Hauser

Misty M Attwood

Mathias Rask-Andersen

Helgi B Schioth

David E Gloriam

Affiliations

Soon will be listed here.

Abstract

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

Citing Articles

Ligand-Induced Biased Activation of GPCRs: Recent Advances and New Directions from In Silico Approaches.

Hashem S, Dougha A, Tuffery P Molecules. 2025; 30(5).

PMID: 40076272 PMC: 11901715. DOI: 10.3390/molecules30051047.

GPR132 regulates the function of NK cells through the Gαs/CSK/ZAP70/NF-κB signaling pathway as a potential immune checkpoint.

Hui X, Xue M, Ren Y, Chen Y, Chen X, Farooq M Sci Adv. 2025; 11(10):eadr9395.

PMID: 40043109 PMC: 11881902. DOI: 10.1126/sciadv.adr9395.

GPCR drug discovery: new agents, targets and indications.

Lorente J, Sokolov A, Ferguson G, Schioth H, Hauser A, Gloriam D Nat Rev Drug Discov. 2025; .

PMID: 40033110 DOI: 10.1038/s41573-025-01139-y.

Regulation of CXCR4 function by S1P through heteromerization.

Kim H, Jeong J, Huh W Cell Commun Signal. 2025; 23(1):111.

PMID: 40012038 PMC: 11863771. DOI: 10.1186/s12964-025-02099-x.

G-Protein-Coupled Receptor (GPCR) Signaling and Pharmacology in Metabolism: Physiology, Mechanisms, and Therapeutic Potential.

Cho Y, Kim S, Kim P, Jo M, Park S, Choi Y Biomolecules. 2025; 15(2).

PMID: 40001594 PMC: 11852853. DOI: 10.3390/biom15020291.

References

Freimann K, Kurrikoff K, Langel U . Galanin receptors as a potential target for neurological disease. Expert Opin Ther Targets. 2015; 19(12):1665-76. DOI: 10.1517/14728222.2015.1072513. View

Foster S, Roura E, Thomas W . Extrasensory perception: odorant and taste receptors beyond the nose and mouth. Pharmacol Ther. 2013; 142(1):41-61. DOI: 10.1016/j.pharmthera.2013.11.004. View

Costa-Neto C, Parreiras-E-Silva L, Bouvier M . A Pluridimensional View of Biased Agonism. Mol Pharmacol. 2016; 90(5):587-595. DOI: 10.1124/mol.116.105940. View

Bowen R, Perry G, Xiong C, Smith M, Atwood C . A clinical study of lupron depot in the treatment of women with Alzheimer's disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks. J Alzheimers Dis. 2014; 44(2):549-60. DOI: 10.3233/JAD-141626. View

Du C, Xie X . G protein-coupled receptors as therapeutic targets for multiple sclerosis. Cell Res. 2012; 22(7):1108-28. PMC: 3750109. DOI: 10.1038/cr.2012.87. View

Lauffer L, Iakoubov R, Brubaker P . GPR119: "double-dipping" for better glycemic control. Endocrinology. 2008; 149(5):2035-7. DOI: 10.1210/en.2008-0182. View

Mancini A, Poitout V . GPR40 agonists for the treatment of type 2 diabetes: life after 'TAKing' a hit. Diabetes Obes Metab. 2015; 17(7):622-9. DOI: 10.1111/dom.12442. View

Kaku K, Enya K, Nakaya R, Ohira T, Matsuno R . Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial. Diabetes Obes Metab. 2015; 17(7):675-81. PMC: 4676912. DOI: 10.1111/dom.12467. View

Jazayeri A, Dias J, Marshall F . From G Protein-coupled Receptor Structure Resolution to Rational Drug Design. J Biol Chem. 2015; 290(32):19489-95. PMC: 4528114. DOI: 10.1074/jbc.R115.668251. View

10.

Zhang R, Xie X . Tools for GPCR drug discovery. Acta Pharmacol Sin. 2012; 33(3):372-84. PMC: 3312097. DOI: 10.1038/aps.2011.173. View

11.

Hamann J, Aust G, Arac D, Engel F, Formstone C, Fredriksson R . International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev. 2015; 67(2):338-67. PMC: 4394687. DOI: 10.1124/pr.114.009647. View

12.

Lang R, Gundlach A, Holmes F, Hobson S, Wynick D, Hokfelt T . Physiology, signaling, and pharmacology of galanin peptides and receptors: three decades of emerging diversity. Pharmacol Rev. 2014; 67(1):118-75. DOI: 10.1124/pr.112.006536. View

13.

Nygaard R, Zou Y, Dror R, Mildorf T, Arlow D, Manglik A . The dynamic process of β(2)-adrenergic receptor activation. Cell. 2013; 152(3):532-42. PMC: 3586676. DOI: 10.1016/j.cell.2013.01.008. View

14.

Psichas A, Reimann F, Gribble F . Gut chemosensing mechanisms. J Clin Invest. 2015; 125(3):908-17. PMC: 4362249. DOI: 10.1172/JCI76309. View

15.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

16.

Neves S, Ram P, Iyengar R . G protein pathways. Science. 2002; 296(5573):1636-9. DOI: 10.1126/science.1071550. View

17.

Jacobson K . New paradigms in GPCR drug discovery. Biochem Pharmacol. 2015; 98(4):541-55. PMC: 4967540. DOI: 10.1016/j.bcp.2015.08.085. View

18.

Kolar G, Grote S, Yosten G . Targeting orphan G protein-coupled receptors for the treatment of diabetes and its complications: C-peptide and GPR146. J Intern Med. 2016; 281(1):25-40. PMC: 6092955. DOI: 10.1111/joim.12528. View

19.

Nicoletti F, Bruno V, Ngomba R, Gradini R, Battaglia G . Metabotropic glutamate receptors as drug targets: what's new?. Curr Opin Pharmacol. 2014; 20:89-94. DOI: 10.1016/j.coph.2014.12.002. View

20.

Bufe B, Schumann T, Kappl R, Bogeski I, Kummerow C, PodgOrska M . Recognition of bacterial signal peptides by mammalian formyl peptide receptors: a new mechanism for sensing pathogens. J Biol Chem. 2015; 290(12):7369-87. PMC: 4367248. DOI: 10.1074/jbc.M114.626747. View