1521-0081/72/1/1–49$35.00 https://doi.org/10.1124/pr.118.016899 PHARMACOLOGICAL REVIEWS Pharmacol Rev 72:1–49, January 2020 Copyright © 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: PAUL A. INSEL G Protein–Coupled Receptors in Asthma Therapy: Pharmacology and Drug Actions Stacy Gelhaus Wendell, Hao Fan, and Cheng Zhang Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.) Abstract. ..................................................................................... 3 Significance Statement ....................................................................... 3 I. Asthma and Asthma Therapy................................................................. 3 A. Epidemiology, Pathology, and Pathophysiology of Asthma . ................................ 3 1. Type 2-High Endotype Pathophysiology ................................................ 4 2. Type 2-Low Endotype Pathophysiology................................................. 5 B. Current Treatment Methods . ............................................................. 5 1. Long-Term Control Medications ....................................................... 5 Downloaded from a. Inhaled corticosteroids ............................................................. 5 b. Long-acting b2-agonists ............................................................ 6 c. Long-acting muscarinic antagonists................................................. 6 d. Leukotriene modifiers and leukotriene receptor antagonists ......................... 7 e. Theophylline ....................................................................... 7 by guest on November 25, 2019 f. Cromolyn . ......................................................................... 7 2. Quick-Relief (Rescue) Medications ..................................................... 7 a. Oral and intravenous corticosteroids................................................ 7 b. Short-acting b2-agonists ............................................................ 7 c. Short-acting muscarinic antagonists ................................................ 7 3. Biologic Agents........................................................................ 7 C. Inhalation Therapy ....................................................................... 7 D. Preclinical Models of Asthma ............................................................. 8 E. G Protein–Coupled Receptors as Important Drug Targets in Asthma. .................... 9 II. b2-Adrenergic Receptor and b2-Agonists.......................................................10 A. Pathophysiological Roles and Signaling of the b2-Adrenergic Receptor in Asthma . ........10 B. Currently Used b2-Agonist Drugs and Their Pharmacological Properties ...................11 C. Structural Insights into Drug Action ......................................................13 1. Chemical Structures of b2-Agonists . .................................................13 2. Structural Insights into the Pharmacological Properties of b2-Agonists . ..............13 a. Ligand efficacy. ...................................................................13 b. Duration of action..................................................................14 c. Receptor–subtype selectivity. .......................................................17 d. Biased signaling ...................................................................17 III. Muscarinic Acetylcholine Receptors and Muscarinic Antagonists...............................17 A. Pathophysiological Roles and Signaling of Muscarinic Receptors in Asthma . ..............17 Address correspondence to: Dr. Hao Fan, Bioinformatics Institute, A*STAR, 30 Biopolis Street, Matrix #07-01, Singapore 138671. E-mail: [email protected] or Dr. Cheng Zhang, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA 15261. E-mail: [email protected] This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant 1R35GM128641 (to C.Z.)]; the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant R21AI122071 (to S.G.W.)]; and the Biomedical Research Council of A*STAR funding support (to H.F.). https://doi.org/10.1124/pr.118.016899. s This article has supplemental material available at pharmrev.aspetjournals.org. 1 2 Wendell et al. B. Currently Used Muscarinic Antagonist Drugs and Their Pharmacological Properties .......18 C. Structural Insights into Drug Action ......................................................19 1. Chemical Structures of Clinically Used Muscarinic Antagonists ........................19 2. Structural Insights into the Pharmacological Properties of Clinically Used Muscarinic Antagonists. .............................................................19 a. Ligand efficacy. ...................................................................20 b. Receptor subtype selectivity in the orthosteric site . ................................22 c. The structural basis for the action of allosteric modulators as potential novel asthma drugs . ...................................................................22 IV. Cysteinyl Leukotriene Receptors and Leukotriene Antagonists ................................23 A. Pathophysiological Roles and Signaling of Cysteinyl Leukotriene Receptors in Asthma . 23 1. Cysteinyl Leukotriene Synthesis .......................................................23 2. Pathophysiological Roles and Signaling of Cysteinyl Leukotriene Receptors .............23 B. Currently Used Leukotriene Receptor Antagonist Drugs and Their Pharmacological Properties . ...............................................................................25 1. Montelukast. .........................................................................26 2. Pranlukast . .........................................................................27 3. Zafirlukast . .........................................................................27 C. Structural Insights into Drug Action ......................................................27 V. Potential G Protein–Coupled Receptor–Targeting Drugs for Asthma in Late-Stage Clinical Trials . .....................................................................................28 A. New G Protein–Coupled Receptor Targets for Developing Asthma Drugs...................28 B. Prostaglandin D2 Receptor 2 and Its Antagonists..........................................29 1. The Roles of Prostaglandin D2 Receptor 2 in Asthma. ................................29 2. Prostaglandin D2 Receptor 2 Antagonists . ...........................................30 3. Structural Insights into the Action of Prostaglandin D2 Receptor 2 Antagonists . ........32 C. Potential Asthma Drugs Acting on Existing Asthma Targets...............................32 1. Abediterol.............................................................................33 2. Bedoradrine . .........................................................................33 VI. Future Perspectives . .........................................................................34 A. G Protein–Coupled Receptor Drugs in Early Stage of Development ........................34 1. AZD8871 as a Dual-Action Ligand of Muscarinic Receptors and b2-Adrenergic Receptor ..............................................................................34 2. CVT-6883 as an Antagonist of Adenosine A2B Receptor ................................35 3. Toreforant as an Antagonist of Histamine H4 Receptor. ................................35 4. FX125L ...............................................................................35 B. New Opportunities in G Protein–Coupled Receptor Drug Development for Asthma . ........35 1. New Targets and Novel Therapeutic Methods ..........................................36 2. Structure-Based Drug Design. .......................................................36 3. G Protein–Coupled Receptor Antibodies as Therapeutics ...............................36 References ...................................................................................37 ABBREVIATIONS: 5-LOX, 5-lipoxygenase; 7TM, seven-transmembrane helix; AA, arachidonic acid; AHR, airway hyperresponsiveness; AIA, aspirin-induced asthma; ALX, lipoxin A4 receptor; ASM, airway smooth muscle; b1AR, b1-adrenergic receptor; b2AR, b2-adrenergic receptor; b3AR, b3-adrenergic receptor; BLT, leukotriene receptor; COPD, chronic obstructive pulmonary disease; CysLT, cysteinyl leuko- triene; CysLTR, CysLT receptor; DC, dendritic cell; DP1, PGD2 receptor 1; DP2, PGD2 receptor 2; ECL, extracellular loop; EIA, exercise- induced asthma; FDA, Food and Drug Administration; FPR, formyl peptide receptor; Gas, a subunit of Gs; GINA, Global Initiative for Asthma; GPCR, G protein–coupled receptor; H4R, histamine 4 receptor; HDM, house dust mite; ICS, inhaled corticosteroid; IL, interleukin; ILC2, group 2 innate lymphoid cell; LABA, long-acting b2-agonist; LAMA, long-acting muscarinic antagonist; LTA4, leukotriene A4; LTB4, leuko- triene B4; LTC4, leukotriene C4; LTD4, leukotriene D4; LTE4, leukotriene E4; LTRA, leukotriene receptor