Abstract
G protein-coupled receptors (GPCRs) form one of the largest drug target families, reflecting their involvement in numerous pathophysiological processes. In this Review, we analyse drug discovery trends for the GPCR superfamily, covering compounds, targets and indications that have reached regulatory approval or that are being investigated in clinical trials. We find that there are 516 approved drugs targeting GPCRs, making up 36% of all approved drugs. These drugs act on 121 GPCR targets, one-third of all non-sensory GPCRs. Furthermore, 337 agents targeting 133 GPCRs, including 30 novel targets, are being investigated in clinical trials. Notably, 165 of these agents are approved drugs being tested for additional indications and novel agents are increasingly allosteric modulators and biologics. Remarkably, diabetes and obesity drugs targeting GPCRs had sales of nearly US $30 billion in 2023 and the numbers of clinical trials for GPCR modulators in the metabolic diseases, oncology and immunology areas are increasing strongly. Finally, we highlight the potential of untapped target–disease associations and pathway-biased signalling. Overall, this Review provides an up-to-date reference for the drugged and potentially druggable GPCRome to inform future GPCR drug discovery and development.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
27,99 € / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
209,00 € per year
only 17,42 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nordstrom, K. J., Sallman Almen, M., Edstam, M. M., Fredriksson, R. & Schioth, H. B. Independent HHsearch, Needleman–Wunsch-based, and motif analyses reveal the overall hierarchy for most of the G protein-coupled receptor families. Mol. Biol. Evol. 28, 2471–2480 (2011).
Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schioth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug. Discov. 16, 829–842 (2017).
Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug. Discov. 16, 19–34 (2017).
Wicks, C., Hudlicky, T. & Rinner, U. Morphine alkaloids: history, biology, and synthesis. Alkaloids Chem. Biol. 86, 145–342 (2021).
Holmstedt, B., Wassén, S. H. & Schultes, R. E. Jaborandi: an interdisciplinary appraisal. J. Ethnopharmacol. 1, 3–21 (1979).
Ahlquist, R. P. A study of the adrenotropic receptors. Am. J. Physiol. 153, 586–600 (1948).
Hargrave, P. A. et al. The structure of bovine rhodopsin. Biophys. Struct. Mech. 9, 235–244 (1983).
Dixon, R. A. et al. Cloning of the gene and cDNA for mammalian β-adrenergic receptor and homology with rhodopsin. Nature 321, 75–79 (1986).
Dohlman, H. G., Caron, M. G. & Lefkowitz, R. J. A family of receptors coupled to guanine nucleotide regulatory proteins. Biochemistry 26, 2657–2664 (1987).
Lin, H. H. G-protein-coupled receptors and their (bio)chemical significance win 2012 Nobel Prize in Chemistry. Biomed. J. 36, 118–124 (2013).
Roth, B. L. & Chuang, D. M. Multiple mechanisms of serotonergic signal transduction. Life Sci. 41, 1051–1064 (1987).
Fisher, A. et al. Selective signaling via unique M1 muscarinic agonists. Ann. N. Y. Acad. Sci. 695, 300–303 (1993).
Christopoulos, A. et al. International Union of Basic and Clinical Pharmacology. XC. Multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol. Rev. 66, 918–947 (2014).
Kenakin, T. Biased receptor signaling in drug discovery. Pharmacol. Rev. 71, 267–315 (2019).
Smith, J. S., Lefkowitz, R. J. & Rajagopal, S. Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug. Discov. 17, 243–260 (2018).
Palczewski, K. et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739–745 (2000).
Cherezov, V. et al. High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318, 1258–1265 (2007).
Rasmussen, S. G. F. et al. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450, 383–387 (2007).
Congreve, M., de Graaf, C., Swain, N. A. & Tate, C. G. Impact of GPCR structures on drug discovery. Cell 181, 81–91 (2020).
Lopez-Balastegui, M. et al. Relevance of G protein-coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation. Br J Pharmacol. https://doi.org/10.1111/bph.16495 (2024).
Caroli, J. et al. An online GPCR drug discovery resource. Preprint at bioRxiv https://doi.org/10.1101/2025.01.11.632537 (2025).
Tobin, A. B. A golden age of muscarinic acetylcholine receptor modulation in neurological diseases. Nat. Rev. Drug. Discov. 23, 743–758 (2024).
Kingwell, K. FDA approves first schizophrenia drug with new mechanism of action since 1950s. Nat. Rev. Drug Discov. 23, 803 (2024).
Bassilana, F., Nash, M. & Ludwig, M.-G. Adhesion G protein-coupled receptors: opportunities for drug discovery. Nat. Rev. Drug. Discov. 18, 869–884 (2019).
Alhiary, R. et al. Patents and regulatory exclusivities on GLP-1 receptor agonists. JAMA 330, 650–657 (2023).
Roth, B. L., Sheffler, D. J. & Kroeze, W. K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug. Discov. 3, 353–359 (2004).
Zhou, Q. et al. Weight loss blockbuster development: a role for unimolecular polypharmacology. Annu. Rev. Pharmacol. Toxicol. https://doi.org/10.1146/annurev-pharmtox-061324-011832 (2024).
Su, M. et al. Structural basis of agonist specificity of ɑ1A-adrenergic receptor. Nat. Commun. 14, 4819 (2023).
Fan, L. et al. Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands. Nat. Commun. 11, 1074 (2020).
Kruse, A. C. et al. Muscarinic receptors as model targets and antitargets for structure-based ligand discovery. Mol. Pharmacol. 84, 528–540 (2013).
Simon, I. A. et al. Ligand selectivity hotspots in serotonin GPCRs. Trends Pharmacol. Sci. 44, 978–990 (2023).
Keam, S. J. Gepirone extended-release: first approval. Drugs 83, 1723–1728 (2023).
He, J. et al. ASD2023: towards the integrating landscapes of allosteric knowledgebase. Nucleic Acids Res. 52, D376–D383 (2023).
Swanson, C. J. et al. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat. Rev. Drug. Discov. 4, 131–144 (2005).
Changeux, J. P. & Christopoulos, A. Allosteric modulation as a unifying mechanism for receptor function and regulation. Cell 166, 1084–1102 (2016).
O’Brien, E. S. et al. A µ-opioid receptor modulator that works cooperatively with naloxone. Nature 631, 686–693 (2024).
Persechino, M., Hedderich, J. B., Kolb, P. & Hilger, D. Allosteric modulation of GPCRs: from structural insights to in silico drug discovery. Pharmacol. Ther. 237, 108242 (2022).
Cheng, L. et al. Structure, function and drug discovery of GPCR signaling. Mol. Biomed. 4, 46 (2023).
Conflitti, P. et al. Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery. Nat. Rev. Drug Discov. https://doi.org/10.1038/s41573-024-01083-3 (2025).
Peter, S. et al. Comparative study of allosteric GPCR binding sites and their ligandability potential. J. Chem. Inf. Model. 64, 8176–8192 (2024).
Pandy-Szekeres, G. et al. GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources. Nucleic Acids Res. 51, D395–D402 (2023).
Zhang, M. et al. G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery. Signal. Transduct. Target. Ther. 9, 88 (2024).
Zhang, L., Mobbs, J. I., May, L. T., Glukhova, A. & Thal, D. M. The impact of cryo-EM on determining allosteric modulator-bound structures of G protein-coupled receptors. Curr. Opin. Struct. Biol. 79, 102560 (2023).
Thal, D. M., Glukhova, A., Sexton, P. M. & Christopoulos, A. Structural insights into G-protein-coupled receptor allostery. Nature 559, 45–53 (2018).
Hutchings, C. J., Koglin, M., Olson, W. C. & Marshall, F. H. Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat. Rev. Drug. Discov. 16, 787–810 (2017).
Killion, E. A. et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci. Transl. Med. 10, eaat3392 (2018).
Véniant, M. M. et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat. Metab. 6, 290–303 (2024).
Pettus, J. et al. Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial. Nat. Med. 28, 2092–2099 (2022).
Salom, D., Wu, A., Liu, C. C. & Palczewski, K. The impact of nanobodies on G protein-coupled receptor structural biology and their potential as therapeutic agents. Mol. Pharmacol. 106, 155–163 (2024).
Carter, P. J. & Rajpal, A. Designing antibodies as therapeutics. Cell 185, 2789–2805 (2022).
Vasile, S. et al. Evolution of angiotensin peptides and peptidomimetics as angiotensin II receptor type 2 (AT2) receptor agonists. Biomolecules 10, 649 (2020).
Stępnicki, P., Kondej, M., Koszła, O., Żuk, J. & Kaczor, A. A. Multi-targeted drug design strategies for the treatment of schizophrenia. Expert. Opin. Drug. Discov. 16, 101–114 (2021).
Hughes, C. E. & Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 285, 2944–2971 (2018).
Liu, H. et al. Chemokines and chemokine receptors: a new strategy for breast cancer therapy. Cancer Med. 9, 3786–3799 (2020).
Braoudaki, M. et al. Chemokines and chemokine receptors in colorectal cancer; multifarious roles and clinical impact. Semin. Cancer Biol. 86, 436–449 (2022).
Ha, H., Debnath, B. & Neamati, N. Role of the CXCL8–CXCR1/2 axis in cancer and inflammatory diseases. Theranostics 7, 1543–1588 (2017).
Xiong, N., Fu, Y., Hu, S., Xia, M. & Yang, J. CCR10 and its ligands in regulation of epithelial immunity and diseases. Protein Cell 3, 571–580 (2012).
Huynh, C. et al. A multipurpose first-in-human study with the novel CXCR7 antagonist ACT-1004-1239 using CXCL12 plasma concentrations as target engagement biomarker. Clin. Pharmacol. Ther. 109, 1648–1659 (2021).
Boof, M. L. et al. Pharmacokinetics, pharmacodynamics and safety of the novel C–X–C chemokine receptor 3 antagonist ACT-777991: results from the first-in-human study in healthy adults. Br. J. Clin. Pharmacol. 90, 588–599 (2024).
Cocchi, F. et al. Identification of RANTES, MIP-1ɑ, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811–1815 (1995).
Feng, Y., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996).
Fadel, H. & Temesgen, Z. Maraviroc. Drugs Today 43, 749–758, (2007).
De Clercq, E. Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration. Antivir. Chem. Chemother. 27, 2040206619829382 (2019).
Horuk, R. Chemokine receptor antagonists: overcoming developmental hurdles. Nat. Rev. Drug. Discov. 8, 23–33 (2009).
Sonnweber, T., Pizzini, A., Nairz, M., Weiss, G. & Tancevski, I. Arachidonic acid metabolites in cardiovascular and metabolic diseases. Int. J. Mol. Sci. 19, 3285 (2018).
Jore, M. M. et al. Structural basis for therapeutic inhibition of complement C5. Nat. Struct. Mol. Biol. 23, 378–386 (2016).
Roversi, P. et al. Bifunctional lipocalin ameliorates murine immune complex-induced acute lung injury. J. Biol. Chem. 288, 18789–18802 (2013).
Sadik, C. D. et al. Evaluation of nomacopan for treatment of bullous pemphigoid: a phase 2a nonrandomized controlled trial. JAMA Dermatol. 158, 641–649 (2022).
Edinoff, A. N. et al. Cebranopadol for the treatment of chronic pain. Curr. Pain. Headache Rep. 27, 615–622 (2023).
Davenport, A. P. et al. International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65, 967–986 (2013).
Laun, A. S., Shrader, S. H., Brown, K. J. & Song, Z. H. GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. Acta Pharmacol. Sin. 40, 300–308 (2019).
Ali, S., Wang, P., Murphy, R. E., Allen, J. A. & Zhou, J. Orphan GPR52 as an emerging neurotherapeutic target. Drug. Discov. Today 29, 103922 (2024).
Gao, W. S. et al. DOK3 is involved in microglial cell activation in neuropathic pain by interacting with GPR84. Aging 13, 389–410 (2020).
Brice, N. L. et al. Development of CVN424: a selective and novel GPR6 inverse agonist effective in models of Parkinson disease. J. Pharmacol. Exp. Ther. 377, 407–416 (2021).
Gembardt, F., Grajewski, S., Vahl, M., Schultheiss, H. P. & Walther, T. Angiotensin metabolites can stimulate receptors of the Mas-related genes family. Mol. Cell Biochem. 319, 115–123 (2008).
Santos, R. A. S. et al. The ACE2/angiotensin-(1–7)/MAS axis of the renin–angiotensin system: focus on angiotensin-(1–7). Physiol. Rev. 98, 505–553 (2018).
Self, W. H. et al. Renin–angiotensin system modulation with synthetic angiotensin (1–7) and angiotensin II type 1 receptor-biased ligand in adults with COVID-19: two randomized clinical trials. JAMA 329, 1170–1182 (2023).
Lin, X. et al. Structural basis of ligand recognition and self-activation of orphan GPR52. Nature 579, 152–157 (2020).
Fan, Y. et al. Allosteric coupling between G-protein binding and extracellular ligand binding sites in GPR52 revealed by 19F-NMR and cryo-electron microscopy. MedComm 4, e260 (2023).
Liu, H. et al. Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84. Nat. Commun. 14, 3271 (2023).
Yang, F. et al. Structure, function and pharmacology of human itch receptor complexes. Nature 600, 164–169 (2021).
Cao, C. et al. Structure, function and pharmacology of human itch GPCRs. Nature 600, 170–175 (2021).
Pushpakom, S. et al. Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug. Discov. 18, 41–58 (2019).
Vokinger, K. N. et al. Therapeutic value of first versus supplemental indications of drugs in US and Europe (2011–20): retrospective cohort study. BMJ 382, e074166 (2023).
Ghazy, A. A. et al. Role of oxytocin in different neuropsychiatric, neurodegenerative, and neurodevelopmental disorders. Rev. Physiol. Biochem. Pharmacol. 186, 95–134 (2023).
Black, J. W., Crowther, A. F., Shanks, R. G., Smith, L. H. & Dornhorst, A. C. A new adrenergic β-receptor antagonist. Lancet 1, 1080–1081 (1964).
Léauté-Labrèze, C. et al. Propranolol for severe hemangiomas of infancy. N. Engl. J. Med. 358, 2649–2651 (2008).
Chung, E. K. Wolff–Parkinson–White syndrome—current views. Am. J. Med. 62, 252–266 (1977).
Lin, Y. et al. β-Adrenergic receptor blocker propranolol triggers anti-tumor immunity and enhances irinotecan therapy in mice colorectal cancer. Eur. J. Pharmacol. 949, 175718 (2023).
Shepard, M. J. et al. Repurposing propranolol as an antitumor agent in von Hippel–Lindau disease. J. Neurosurg. 131, 1106–1114 (2018).
Sinichi, F. et al. Pentoxifylline as adjunctive therapy in cognitive deficits and symptoms of schizophrenia: a randomized double-blind placebo-controlled clinical trial. J. Psychopharmacol. 37, 1003–1010 (2023).
Srivastava, A. B. & Gold, M. S. Naltrexone: A history and future directions. Cerebrum cer-13-18 (2018).
Pitt, B., Tate, A. M., Gluck, D., Rosenson, R. S. & Goonewardena, S. N. Repurposing low-dose naltrexone for the prevention and treatment of immunothrombosis in COVID-19. Eur. Heart J. Cardiovasc. Pharmacother. 8, 402–405 (2022).
Isman, A. et al. Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain Behav. Immun. Health 36, 100733 (2024).
Grilo, C. M. et al. Naltrexone–bupropion and behavior therapy, alone and combined, for binge-eating disorder: randomized double-blind placebo-controlled trial. Am. J. Psychiatry 179, 927–937 (2022).
Pagano, C. et al. Cannabinoids: Therapeutic use in clinical practice. Int. J. Mol. Sci. 23, 3344 (2022).
Robles-Osorio, M. L. et al. Basis and design of a randomized clinical trial to evaluate the effect of levosulpiride on retinal alterations in patients with diabetic retinopathy and diabetic macular edema. Front. Endocrinol. 9, 242 (2018).
Koch, M. W. et al. Repurposing domperidone in secondary progressive multiple sclerosis: a Simon 2-stage phase 2 futility trial. Neurology 96, e2313–e2322 (2021).
Green, A. J. et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet 390, 2481–2489 (2017).
Kocot, J. et al. Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis. Preprint at medRxiv https://doi.org/10.1101/2024.04.09.24305506 (2024).
Keating, G. M. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs 75, 1119–1130 (2015).
Miller, L. J. Prazosin for the treatment of posttraumatic stress disorder sleep disturbances. Pharmacotherapy 28, 656–666 (2008).
Schultz, J. L. et al. A pilot to assess target engagement of terazosin in Parkinson’s disease. Parkinsonism Relat. Disord. 94, 79–83 (2022).
Zhang, G. C. et al. β2-Adrenergic receptor agonist corrects immune thrombocytopenia by reestablishing the homeostasis of T cell differentiation. J. Thromb. Haemost. 21, 1920–1933 (2023).
Fumagalli, C., Maurizi, N., Marchionni, N. & Fornasari, D. β-Blockers: their new life from hypertension to cancer and migraine. Pharmacol. Res. 151, 104587 (2020).
Byers, P. H. et al. Diagnosis, natural history, and management in vascular Ehlers–Danlos syndrome. Am. J. Med. Genet. 175, 40–47 (2017).
Köhne, S., Hillemacher, T., Glahn, A. & Bach, P. Emerging drugs in phase II and III clinical development for the treatment of alcohol use disorder. Expert Opin. Emerg. Drugs 29, 219–232 (2024).
Smith, N. H. & Howze, E. H. Inventorying community health promotion and risk reduction services: Virginia’s approach. Health Educ. Q. 14, 403–410 (1987).
Zhang, Z. X. et al. Clinical outcomes of recommended active pharmacotherapy agents from NICE guideline for post-traumatic stress disorder: network meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 125, 110754 (2023).
Smith, T. J., Loprinzi, C. L. & Deville, C. Oxybutynin for hot flashes due to androgen deprivation in men. N. Engl. J. Med. 378, 1745–1746 (2018).
Foster, S. R. et al. Discovery of human signaling systems: pairing peptides to G protein-coupled receptors. Cell 179, 895–908.e21 (2019).
Mehrotra, S., Kalyan Bg, P., Nayak, P. G., Joseph, A. & Manikkath, J. Recent progress in the oral delivery of therapeutic peptides and proteins: overview of pharmaceutical strategies to overcome absorption hurdles. Adv. Pharm. Bull. 14, 11–33 (2024).
Jia, Y., Liu, Y., Feng, L., Sun, S. & Sun, G. Role of glucagon and its receptor in the pathogenesis of diabetes. Front. Endocrinol. 13, 928016 (2022).
Hammoud, R. & Drucker, D. J. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat. Rev. Endocrinol. 19, 201–216 (2023).
Drucker, D. J. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 27, 740–756 (2018).
Gutgesell, R. M., Nogueiras, R., Tschöp, M. H. & Müller, T. D. Dual and triple incretin-based co-agonists: novel therapeutics for obesity and diabetes. Diabetes Ther. 15, 1069–1084 (2024).
Folli, F. et al. Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. Am. J. Physiol. Endocrinol. Metab. 325, E595–E609 (2023).
Nauck, M. A. & D’Alessio, D. A. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc. Diabetol. 21, 169 (2022).
Romero-Gómez, M. et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J. Hepatol. 79, 888–897 (2023).
Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N. Engl. J. Med. 389, 514–526 (2023).
Abdelmalek, M. F. et al. A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis—study design and rationale of HM-TRIA-201 study. Contemp. Clin. Trials 130, 107176 (2023).
Wang, C. et al. The orexin/receptor system: molecular mechanism and therapeutic potential for neurological diseases. Front. Mol. Neurosci. 11, 220 (2018).
Maness, E. B., Blumenthal, S. A. & Burk, J. A. Dual orexin/hypocretin receptor antagonism attenuates NMDA receptor hypofunction-induced attentional impairments in a rat model of schizophrenia. Behav. Brain Res. 450, 114497 (2023).
Glen, A. et al. Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist. Bioorg. Med. Chem. Lett. 100, 129629 (2024).
Johnson & Johnson pivotal study of seltorexant shows statistically significant and clinically meaningful improvement in depressive symptoms and sleep disturbance outcomes. Johnson & Johnson (29 May 2024); https://www.jnj.com/media-center/press-releases/johnson-johnson-pivotal-study-of-seltorexant-shows-statistically-significant-and-clinically-meaningful-improvement-in-depressive-symptoms-and-sleep-disturbance-outcomes.
Harrison, J. E., Weber, S., Jakob, R. & Chute, C. G. ICD-11: an International Classification of Diseases for the twenty-first century. BMC Med. Inform. Decis. Mak. 21, 206 (2021).
Li, Y., Li, B., Chen, W. D. & Wang, Y. D. Role of G-protein coupled receptors in cardiovascular diseases. Front. Cardiovasc. Med. 10, 1130312 (2023).
Wendell, S. G., Fan, H. & Zhang, C. G protein-coupled receptors in asthma therapy: pharmacology and drug action. Pharmacol. Rev. 72, 1–49 (2020).
Wong, T. S. et al. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Signal. Transduct. Target. Ther. 8, 177 (2023).
Aronson, J. K. & Green, A. R. Me-too pharmaceutical products: history, definitions, examples, and relevance to drug shortages and essential medicines lists. Br. J. Clin. Pharmacol. 86, 2114–2122 (2020).
Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 73, 17–48 (2023).
Paul, S. M. & Potter, W. Z. Finding new and better treatments for psychiatric disorders. Neuropsychopharmacology 49, 3–9 (2024).
Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019).
Jones-Tabah, J. Targeting G protein-coupled receptors in the treatment of Parkinson’s disease. J. Mol. Biol. 435, 167927 (2023).
Larsen, A. T., Sonne, N., Andreassen, K. V., Karsdal, M. A. & Henriksen, K. The calcitonin receptor plays a major role in glucose regulation as a function of dual amylin and calcitonin receptor agonist therapy. J. Pharmacol. Exp. Ther. 374, 74–83 (2020).
Dhillon, S. Semaglutide: first global approval. Drugs 78, 275–284 (2018).
Syed, Y. Y. Tirzepatide: first approval. Drugs 82, 1213–1220 (2022).
Hyland, M. H. & Cohen, J. A. Fingolimod. Neurol. Clin. Pract. 1, 61–65 (2011).
Lamb, Y. N. Ozanimod: first approval. Drugs 80, 841–848 (2020).
Al-Salama, Z. T. Siponimod: first global approval. Drugs 79, 1009–1015 (2019).
Markham, A. Ponesimod: first approval. Drugs 81, 957–962 (2021).
Adachi, K. & Chiba, K. FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology. Perspect. Medicin. Chem. 1, 11–23 (2007).
Kovarik, J. M. et al. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J. Clin. Pharmacol. 44, 532–537 (2004).
Scott, F. L. et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br. J. Pharmacol. 173, 1778–1792 (2016).
Olsson, T. et al. Oral ponesimod in relapsing–remitting multiple sclerosis: a randomised phase II trial. J. Neurol. Neurosurg. Psychiatry 85, 1198–1208 (2014).
Scott, L. J. Siponimod: a review in secondary progressive multiple sclerosis. CNS Drugs 34, 1191–1200 (2020).
McGinley, M. P. & Cohen, J. A. Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions. Lancet 398, 1184–1194 (2021).
Lee, A. Avacopan: first approval. Drugs 82, 79–85 (2022).
Young, D., Waitches, G., Birchmeier, C., Fasano, O. & Wigler, M. Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains. Cell 45, 711–719 (1986).
Attwood, M. M., Fabbro, D., Sokolov, A. V., Knapp, S. & Schiöth, H. B. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat. Rev. Drug. Discov. 20, 839–861 (2021).
Hoy, S. M. Glasdegib: first global approval. Drugs 79, 207–213 (2019).
Dubey, A. K., Dubey, S., Handu, S. S. & Qazi, M. A. Vismodegib: the first drug approved for advanced and metastatic basal cell carcinoma. J. Postgrad. Med. 59, 48–50 (2013).
Burness, C. B. Sonidegib: first global approval. Drugs 75, 1559–1566 (2015).
Nüsslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 (1980).
Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science 304, 1755–1759 (2004).
Griffith, J. W., Sokol, C. L. & Luster, A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659–702 (2014).
Mollica Poeta, V., Massara, M., Capucetti, A. & Bonecchi, R. Chemokines and chemokine receptors: new targets for cancer immunotherapy. Front. Immunol. 10, 379 (2019).
Ureshino, H., Kamachi, K. & Kimura, S. Mogamulizumab for the treatment of adult T-cell leukemia/lymphoma. Clin. Lymphoma Myeloma Leuk. 19, 326–331 (2019).
Rodriguez-Otero, P. et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. Blood Cancer J. 14, 24 (2024).
Xiang, Y. et al. The G-protein coupled chemoattractant receptor FPR2 promotes malignant phenotype of human colon cancer cells. Am. J. Cancer Res. 6, 2599–2610 (2016).
Yang, M. et al. G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the β-catenin pathway. Proc. Natl Acad. Sci. USA 102, 6027–6032 (2005).
Smith, J. P., Fonkoua, L. K. & Moody, T. W. The role of gastrin and CCK receptors in pancreatic cancer and other malignancies. Int. J. Biol. Sci. 12, 283–291 (2016).
Pérez-Gómez, E. et al. The orphan receptor GPR55 drives skin carcinogenesis and is upregulated in human squamous cell carcinomas. Oncogene 32, 2534–2542 (2013).
Xu, L. et al. GPR56 plays varying roles in endogenous cancer progression. Clin. Exp. Metastasis 27, 241–249 (2010).
Arora, C. et al. The landscape of cancer-rewired GPCR signaling axes. Cell Genom. 4, 100557 (2024).
Arang, N. & Gutkind, J. S. G protein-coupled receptors and heterotrimeric G proteins as cancer drivers. FEBS Lett. 594, 4201–4232 (2020).
Lee, A. Fezolinetant: first approval. Drugs 83, 1137–1141 (2023).
Hoy, S. M. Mavorixafor: first approval. Drugs 84, 969–975 (2024).
Paul, S. M., Yohn, S. E., Brannan, S. K., Neugebauer, N. M. & Breier, A. Muscarinic receptor activators as novel treatments for schizophrenia. Biol. psychiatry 96, 627–637 (2024).
Syed, Y. Y. Sparsentan: first approval. Drugs 83, 563–568 (2023).
Deeks, E. D. Difelikefalin: first approval. Drugs 81, 1937–1944 (2021).
Mittra, E. S. Neuroendocrine tumor therapy: 177Lu-dotatate. AJR Am. J. Roentgenol. 211, 278–285 (2018).
Sanli, Y. et al. Neuroendocrine tumor diagnosis and management: 68Ga-dotatate PET/CT. AJR Am. J. Roentgenol. 211, 267–277 (2018).
Alrumaihi, F. The multi-functional roles of CCR7 in human immunology and as a promising therapeutic target for cancer therapeutics. Front. Mol. Biosci. 9, 834149 (2022).
Kowalski, T. J. & Sasikumar, T. Melanin-concentrating hormone receptor-1 antagonists as antiobesity therapeutics: current status. Biodrugs 21, 311–321 (2007).
Holanda, V. A. D. et al. Neuropeptide S receptor as an innovative therapeutic target for Parkinson disease. Pharmaceuticals 14, 775 (2021).
Miller, L. J. & Desai, A. J. Metabolic actions of the type 1 cholecystokinin receptor: its potential as a therapeutic target. Trends Endocrinol. Metab. 27, 609–619 (2016).
Xu, F. et al. Identification and target-pathway deconvolution of FFA4 agonists with anti-diabetic activity from Arnebia euchroma (Royle) Johnst. Pharmacol. Res. 163, 105173 (2021).
Ochoa, D. et al. The next-generation Open Targets platform: reimagined, redesigned, rebuilt. Nucleic Acids Res. 51, D1353–D1359 (2023).
Caroli, J. et al. A community biased signaling atlas. Nat. Chem. Biol. 19, 531–535 (2023).
Scharf, M. M. et al. The dark sides of the GPCR tree—research progress on understudied GPCRs. Br. J. Pharmacol. https://doi.org/10.1111/bph.16325 (2024).
Hamann, J. et al. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol. Rev. 67, 338–367 (2015).
Gad, A. A. & Balenga, N. The emerging role of adhesion GPCRs in cancer. ACS Pharmacol. Transl. Sci. 3, 29–42 (2020).
Vizurraga, A., Adhikari, R., Yeung, J., Yu, M. & Tall, G. G. Mechanisms of adhesion G protein-coupled receptor activation. J. Biol. Chem. 295, 14065–14083 (2020).
Krumm, B. & Roth, B. L. A structural understanding of class B GPCR selectivity and activation revealed. Structure 28, 277–279 (2020).
Stoveken, H. M. et al. Dihydromunduletone is a small-molecule selective adhesion G protein-coupled receptor antagonist. Mol. Pharmacol. 90, 214–224 (2016).
Gupte, J. et al. Signaling property study of adhesion G-protein-coupled receptors. FEBS Lett. 586, 1214–1219 (2012).
Seufert, F., Chung, Y. K., Hildebrand, P. W. & Langenhan, T. 7TM ___domain structures of adhesion GPCRs: what’s new and what’s missing? Trends Biochem. Sci. 48, 726–739 (2023).
Hayat, R., Manzoor, M. & Hussain, A. Wnt signaling pathway: a comprehensive review. Cell Biol. Int. 46, 863–877 (2022).
Kozielewicz, P. et al. Structural insight into small molecule action on Frizzleds. Nat. Commun. 11, 414 (2020).
Riccio, G. et al. A negative allosteric modulator of WNT receptor Frizzled 4 switches into an allosteric agonist. Biochemistry 57, 839–851 (2018).
Zhang, W., Lu, W., Ananthan, S., Suto, M. J. & Li, Y. Discovery of novel Frizzled-7 inhibitors by targeting the receptor’s transmembrane ___domain. Oncotarget 8, 91459–91470 (2017).
Epping-Jordan, M. P. et al. Effect of the metabotropic glutamate receptor type 5 negative allosteric modulator dipraglurant on motor and non-motor symptoms of Parkinson’s disease. Cells 12, https://doi.org/10.3390/cells12071004 (2023).
Fuxe, K. & Borroto-Escuela, D. O. Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5. Expert. Opin. Investig. Drugs 24, 1247–1260 (2015).
Metcalf, C. S. et al. Efficacy of mGlu2 -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures. Epilepsia 58, 484–493 (2017).
Blednov, Y. A. & Harris, R. A. Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: relationship to acamprosate actions. Int. J. Neuropsychopharmacol. 11, 775–793 (2008).
Bien, C. G., Braig, S. & Bien, C. I. Antibodies against metabotropic glutamate receptor type 1 in a toddler with acute cerebellitis. J. Neuroimmunol. 348, 577366 (2020).
Mehnert, J. M. et al. A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma. Pigment. Cell Melanoma Res. 31, 534–540 (2018).
Luessen, D. J. & Conn, P. J. Allosteric modulators of metabotropic glutamate receptors as novel therapeutics for neuropsychiatric disease. Pharmacol. Rev. 74, 630–661 (2022).
Liauw, B. W. et al. Conformational fingerprinting of allosteric modulators in metabotropic glutamate receptor 2. eLife 11, e78982 (2022).
Bennett, K. A., Christopher, J. A. & Tehan, B. G. Structure-based discovery and development of metabotropic glutamate receptor 5 negative allosteric modulators. Adv. Pharmacol. 88, 35–58 (2020).
Orgován, Z., Ferenczy, G. G. & Keserű, G. M. Fragment-based approaches for allosteric metabotropic glutamate receptor (mGluR) modulators. Curr. Top. Med. Chem. 19, 1768–1781 (2019).
Wall, M. J. et al. Selective activation of Gɑob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression. Nat. Commun. 13, 4150 (2022).
Willard, F. S. et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 5, e140532 (2020).
Chakravarthy, M. et al. 75-LB: CT-388, a novel once-weekly dual GLP-1 and GIP receptor modulator, is safe, well-tolerated, and produces more than 8% weight loss in four weeks in overweight and obese adults. Diabetes https://doi.org/10.2337/db23-75-LB (2023).
Reversi, A. et al. The oxytocin receptor antagonist atosiban inhibits cell growth via a “biased agonist” mechanism. J. Biol. Chem. 280, 16311–16318 (2005).
Kim, S. H. et al. The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via Gαi signalling. Mol. Cell. Endocrinol. 420, 11–23 (2016).
Jørgensen, A. S. et al. Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization. Commun. Biol. 4, 569 (2021).
Kenakin, T. Bias translation: the final frontier? Br. J. Pharmacol. 181, 1345–1360 (2024).
Gillis, A. et al. Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci. Signal. 13, eaaz3140 (2020).
Kaplan, A. L. et al. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity. Nature 610, 582–591 (2022).
Fink, E. A. et al. Structure-based discovery of nonopioid analgesics acting through the ɑ2A-adrenergic receptor. Science 377, eabn7065 (2022).
Kolb, P. et al. Community guidelines for GPCR ligand bias: IUPHAR review 32. Br. J. Pharmacol. 179, 3651–3674 (2022).
Hauser, A. S. et al. GPCR activation mechanisms across classes and macro/microscales. Nat. Struct. Mol. Biol. 28, 879–888 (2021).
Kotliar, I. B. et al. Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins. Sci. Adv. 10, eado9959 (2024).
Polacco, B. J. et al. Profiling the proximal proteome of the activated μ-opioid receptor. Nat. Chem. Biol. 20, 1133–1143 (2024).
Wright, S. C. et al. GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics. Nat. Commun. 14, 6243 (2023).
Reiner-Link, D., Madsen, J. S., Gloriam, D. E., Brauner-Osborne, H. & Hauser, A. S. Differential G protein activation by the long and short isoforms of the dopamine D2 receptor. Br. J. Pharmacol. https://doi.org/10.1111/bph.16388 (2024).
Kockelkoren, G. et al. Molecular mechanism of GPCR spatial organization at the plasma membrane. Nat. Chem. Biol. 20, 142–150 (2024).
Thompson, M. D. et al. G protein-coupled receptor (GPCR) gene variants and human genetic disease. Crit. Rev. Clin. Lab. Sci. 61, 317–346 (2024).
Janicot, R. et al. Direct interrogation of context-dependent GPCR activity with a universal biosensor platform. Cell 187, 1527–1546.e25 (2024).
Edwards, A. What are the odds of finding a COVID-19 drug from a lab repurposing screen? J. Chem. Inf. Model. 60, 5727–5729 (2020).
Harding, S. D. et al. The IUPHAR/BPS Guide to PHARMACOLOGY in 2024. Nucleic Acids Res. 52, D1438–D1449 (2024).
Knox, C. et al. DrugBank 6.0: the DrugBank Knowledgebase for 2024. Nucleic Acids Res. 52, D1265–D1275 (2024).
Herrera, L. P. T. et al. GPCRdb in 2025: adding odorant receptors, data mapper, structure similarity search and models of physiological ligand complexes. Nucleic Acids Res. 53, D425–D435 (2025).
Kim, S. et al. PubChem 2023 update. Nucleic Acids Res. 51, D1373–D1380 (2023).
Acknowledgements
This work was funded by grants from the Lundbeck Foundation (R383-2022-306) and Novo Nordisk Foundation (NNF23OC0082561) to D.E.G. H.B.S was funded by the Swedish Research Council (2022-00562) and the Novo Nordisk Foundation (NNF22OC0078393). A.S.H. acknowledges funding from the Independent Research Fund Denmark (3122-00044B).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
D.E.G. is a part-time employee and warrant-holder of Kvantify. The other authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Drug Discovery thanks Brian Arey, David Thal and the other, anonymous, reviewers for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Related links
Allosteric Database: https://mdl.shsmu.edu.cn/ASD/
Best-selling pharmaceuticals of 2023 reveal a shift in pharma landscape: https://www.drugdiscoverytrends.com/best-selling-pharmaceuticals-2023
Biased Signalling Atlas: https://biasedsignalingatlas.org/
CenterWatch: http://www.centerwatch.com
ChEMBL: https://www.ebi.ac.uk/chembl
ClinicalTrials.gov: https://clinicaltrials.gov
DrugBank: https://www.drugbank.ca
Drugs@FDA (approvals): https://www.accessdata.fda.gov/scripts/cder/daf
GPCRdb: http://www.gpcrdb.org
GPCRdb structure coverage: https://gpcrdb.org/structure/statistics
Guide To Pharmacology: http://www.guidetopharmacology.org
Illuminating the Druggable Genome programme: https://commonfund.nih.gov/idg
IUPHAR/BPS Guide to Pharmacology latest pairings: https://www.guidetopharmacology.org/latestPairings.jsp
Open Targets: https://www.targetvalidation.org
PDB: https://www.rcsb.org/pdb/home/home.do
Pharos: https://pharos.nih.gov/idg/index
PubMed: https://www.ncbi.nlm.nih.gov/pubmed
Visible Alpha GLP-1 Drug Monitor: blockbusters & up-and-comers: https://visiblealpha.com/blog/visible-alpha-glp-1-drug-monitor-blockbusters-up-and-comers/
Web-based resource dedicated to GPCR drug discovery: https://gpcrdb.org/
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lorente, J.S., Sokolov, A.V., Ferguson, G. et al. GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 24, 458–479 (2025). https://doi.org/10.1038/s41573-025-01139-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41573-025-01139-y
