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Review
, 72 (1), 1-49

G Protein-Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action

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Review

G Protein-Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action

Stacy Gelhaus Wendell et al. Pharmacol Rev.

Abstract

Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein-coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting β 2-agonists are widely used bronchodilators that signal through the activation of the β 2-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D2 receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A2B receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment. SIGNIFICANCE STATEMENT: Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein-coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.

Figures

Fig. 1.
Fig. 1.
Chemical structures of β2-agonists. SABAs, LABAs, and ultra-LABAs are indicated by boxes with green, blue, and red colors, respectively.
Fig. 2.
Fig. 2.
Binding sites for β2-agonists revealed by crystal structures. (A) Crystal structures of human β2AR in complex with epinephrine (Supplemental Material 1-PDB ID 4LDO), BI-167107 (Supplemental Material 1-PDB ID 4LDE), and salmeterol (Supplemental Material 1-PDB ID 6MXT). Polar interactions are shown as dashed lines. Residues in β2AR that interact with each ligand are shown as sticks. (B) Exosite for the binding of the tail group of salmeterol in the crystal structure of human β2AR with salmeterol (Supplemental Material 1-PDB ID 6MXT).
Fig. 3.
Fig. 3.
Chemical structures of currently used muscarinic antagonist drugs. (A) Ipratropium and oxitropium as SAMAs. (B) Tiotropium, aclidinium, umeclidinium, and glycopyrrolate as LAMAs.
Fig. 4.
Fig. 4.
Binding sites in MR crystal structures. (A) Orthosteric sites for tiotropium in the crystal structures of tiotropium-bound M1R (top left, Supplemental Material 1-PDB ID 5CXV), M3R (bottom right, Supplemental Material 1-PDB ID 4DAJ), and M4R (top right, Supplemental Material 1-PDB ID 5DSG), and the orthosteric site for QNB in the crystal structure of M2R (bottom left, Supplemental Material 1-PDB ID 3UON). Polar interactions are shown as dashed lines. (B) Crystal structure of active M2R with the orthosteric agonist iperoxo only (left, Supplemental Material 1-PDB ID 4MQS, allosteric site empty) and crystal structure of active M2R with iperoxo and a PAM named LY2119620 (right, Supplemental Material 1-PDB ID 4MQT). Full agonist iperoxo is in the orthosteric site of both structures.
Fig. 5.
Fig. 5.
Chemical structures of CysLTs and LTRAs.
Fig. 6.
Fig. 6.
Chemical structures of PGD2 and CRTH2 antagonists.
Fig. 7.
Fig. 7.
Orthosteric ligand-binding site in CRTH2. The crystal structures of human CRTH2 bound to fevipiprant (left, Supplemental Material 1-PDB ID 6D26) and CAY10471 (right, Supplemental Material 1-PDB ID 6D27) revealed the molecular details of ligand binding in the orthosteric ligand-binding site.
Fig. 8.
Fig. 8.
Chemical structures of two potential asthma drugs acting on β2AR: (A) abediterol, (B) bedoradrine.
Fig. 9.
Fig. 9.
Chemical structures of three GPCR-targeting ligands that are in early stage of development for asthma. (A) AZD8871, (B) CVT-6883, and (C) toreforant.

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