The future of bronchodilation: looking for new classes of bronchodilators

Abstract

Available bronchodilators can satisfy many of the needs of patients suffering from airway disorders, but they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes.At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.It is likely that if developed, these new classes may be a useful addition to, rather than a substitution of, the bronchodilator therapy currently used, in order to achieve further optimisation of bronchodilation.

FIGURE 1

Synthesis of signalling and functional effects of various G-protein coupled receptors (GPCRs) that have been identified in airway smooth muscle cells. AC: adenylyl cyclase; cAMP: cyclic adenosine monophosphate; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal-regulated kinase; GRK: GPCR kinase; IP₃: inositol-3-phosphate; MAPK: p38 mitogen-activated protein kinase; MLCP: myosin light chain phosphatase; NO: nitric oxide; PDE: phosphodiesterase; PI3K: phosphatidylinositol 3-kinase; PKA: protein kinase A; PKC: protein kinase C; PKD: protein kinase D; PLC: phospholipase C; ROCK: Rho-associated coiled-coil-containing protein kinases; TAS2R: taste type 2 receptor.

FIGURE 2

Potential sites of action of phosphodiesterase (PDE) inhibitors and soluble guanylyl cyclase (sGC) activators in airways smooth muscle and inflammatory cells. AC: adenylyl cyclase; (c)AMP: (cyclic) adenosine monophosphate; (c)GMP: (cyclic) guanosine monophosphate; GC: guanylyl cyclase; NO: nitric oxide; PKG: protein kinase G.

FIGURE 3

Activation of E-prostanoid receptor 4 (EP₄) causes airway relaxation. AC: adenylyl cyclase; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; MLCP: myosin light chain phosphatase.

FIGURE 4

Biased various G-protein coupled receptor (GPCR) signalling. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G-protein- or β-arrestin-mediated downstream signalling. GRK: GPCR kinase.