Table 2.

FDA-approved agents targeting GPCRs with polypharmacological characteristics (2010–2023)

First Approval	Drug	Modes of Action	Indications	References
2023	Sparsentan	Antagonist of AT1R and ETAR	Immunoglobulin A Nephropathy	[280]
2022	Tirzepatide	Agonist of GIPR and GLP-1R	Type 2 Diabetes	[281]
2020	Bencycloquidium Bromide	Antagonist of M1 and M3	Allergic Rhinitis	[282, 283]
2020	Ozanimod	Agonist of S1PRs	Crohn’s Disease, Relapsing-Remitting Multiple Sclerosis, Ulcerative Colitis. Multiple Sclerosis	[284–286]
2020	Fenfluramine	Agonist of 5HT1Rs and 5HT2Rs	Lennox-Gastaut Syndrome, Dravet Syndrome, CDKL5 Deficiency, Seizures	[287–294]
2019	Siponimod	Agonist of S1PR1 and S1PR3-5	Secondary Progressive Multiple Sclerosis, Multiple Sclerosis	[286, 295–299]
2019	Lumateperone	Antagonist of 5HT2Rand D2R	Depression, Schizophrenia	[300, 301]
2018	Revefenacin	Antagonist of muscarinic receptors	Chronic Obstructive Pulmonary Disease	[302]
2017	Dinalbuphine Sebacate	Agonist of κOR; Antagonist of µOR	Pain
2015	Aripiprazole Lauroxil	Agonist of D2R, 5HT1Rs, 5HT2Rs, and 5HT7R; Antagonist of H1R, D4R, and 5HT6R	Schizophrenia	[303–308]
2015	Brexpiprazole	Agonist of 5HT1R and D2R	Agitation, Severe Depressive Disorder, Schizophrenia	[309, 310]
2015	Cariprazine	Agonist of 5HT1R, D2R and D3R; Antagonist of 5HT2R	Severe Depressive Disorder, Bipolar Disorder And Related Disorders, Bipolar 1 Disorder, Schizophrenia	[311–313]
2015	Eluxadoline	Agonist of µOR and κOR; Antagonist of δOR	Diarrhea-Type Irritable Bowel Syndrome, Irritable Bowel Syndrome (IBS)	[314]
2015	Flibanserin	Agonist of 5HT1R; Antagonist of 5HT2R and D4R	Psychosexual Dysfunction	[315]
2013	Vortioxetine	Agonist of 5HT1A - BR; Antagonist of 5HT1DR, 5HT2R, 5HT3R and 5HT7R	Severe Depressive Disorder, Depressive	[315]
2013	Macitentan	Antagonist of ETAR and ETBR	Connective Tissue Disease, Pulmonary Hypertension	[316]
2012	Loxapine	Antagonist of H1R, 5HT2Rs, 5HT6R, 5HT7R, and D2R-D4R	Bipolar Disorder, Bipolar 1 Disorder, Schizophrenia	[304, 317–323]
2011	Motilitone	Agonist of 5HT4R; Antagonist of 5HT3R and D2R	Dyspepsia
2010	Lurasidone	Agonist of 5HT1R; Antagonist of 5HT2R, 5HT7R, D2R, Α2AR and Α2CR	Bipolar Disorder, Bipolar 1 Disorder, Schizophrenia	[324]
2010	Fingolimod	Agonist of S1PR1 and S1PR5; Modulator of S1PR3 and S1PR4	Relapsing-Remitting Multiple Sclerosis, Multiple Sclerosis, The Relapsing Multiple Sclerosis	[325]
2010	Buprenorphine	Agonist of µOR; Antagonist of κOR	Opium Dependence, Opioid-Related Disorder, Pain	[326, 327]