Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD

Abstract

In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective b-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease.

A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity

“…M1, M3, and M5 bind Gq proteins, whereas M2 and M4 bind Gi proteins. There are known pharmacologic antagonists with varying selectivity for the M1-M4 muscarinic subtype receptors (30). Since signaling through M1 and M3 leads to increases in intracellular calcium and PAD4 is a calcium-dependent enzyme implicated in NET formation, we hypothesized that levamisole likely engaged either M1 or M3.…”

Interdicting GqActivation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms

“…Other therapies include leukotriene and muscarinic receptor antagonists that inhibit the activation of Ga q bg heterotrimer (G q )-coupled receptors that mediate the parasympathetic and hormonal signaling regulating bronchomotor tone (Bel, 2013). G proteincoupled receptor (GPCR) antagonists have a somewhat limited efficacy in patients as the activation of multiple G q -coupled receptors contribute to the pathology of the disease (Scadding and Scadding, 2010;Moulton and Fryer, 2011). It is plausible that inhibiting G q activation at the receptor or G protein level would be an advantageous asthma therapeutic as G q -mediated ASM shortening is a primary contributor to bronchotone (Borchers et al, 2003;Pelaia et al, 2008).…”

Targeting Phosphoinositide 3-Kinase γ in Airway Smooth Muscle Cells to Suppress Interleukin-13-Induced Mouse Airway Hyperresponsiveness

“…Excessive activation of different bronchoconstrictor GPCRs, such as muscarinic, serotonin, endothelin B, leukotriene, and proton-sensing OGR1 receptors in ASM, contributes to AHR of asthma (Deshpande and Penn, 2006;Saxena et al, 2011). Drugs targeting specific GPCRs are used as therapies for AHR in asthma (Shore and Moore, 2003;Currie and McLaughlin, 2006;Hanania et al, 2010;Moulton and Fryer, 2011), yet asthma still affects 23 million Americans, causing significant morbidity. The strategy of inhibiting a single GPCR is limited because airway constriction can be induced by different GPCRs simultaneously, thereby having bronchoconstrictor signal redundancy.…”