Abstract
Inhaled β2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. β2-adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the β2-adrenoreceptors (β2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short—acting beta-2 agonists in dog and human bronchi. Although the precise mechanisms by which ASM-024 promotes airway smooth muscle (ASM) relaxation remain unclear, we hypothesized that ASM-024 will attenuate and/or abrogate agonist-induced contraction and remain effective despite β2-AR tachyphylaxis. β2-AR tachyphylaxis was induced with salbutamol, salmeterol and formoterol on guinea pig tracheas. The addition of ASM-024 relaxed concentration-dependently intact or β2-AR desensitized tracheal rings precontracted with methacholine. ASM-024 did not induce any elevation of intracellular cAMP in isolated smooth muscle cells; moreover, blockade of the cAMP pathway with an adenylate cyclase inhibitor had no significant effect on ASM-024-induced guinea pig trachea relaxation. Collectively, these findings show that ASM-024 elicits relaxation of β2-AR desensitized tracheal preparations and suggest that ASM-024 mediates smooth muscle relaxation through a different target and signaling pathway than β2-adrenergic receptor agonists. These findings suggest ASM-024 could potentially provide clinical benefit when used adjunctively with inhaled β2-adrenoreceptor agonists in those patients exhibiting a reduced response to their chronic use.
Highlights
Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway inflammation, airway obstruction and, in asthma, increased airway hyperresponsiveness (AHR) which is manifested by excessive constriction of airway smooth muscle (ASM) [1]
There are no further patents, products in development or marketed products to declare. Respiratory diseases such as asthma and COPD are characterized by airway inflammation, airway obstruction and, in asthma, increased airway hyperresponsiveness (AHR) which is manifested by excessive constriction of airway smooth muscle (ASM) [1]
In isometric in vitro studies, ASM-024 caused a dose-related relaxation of dog bronchi contracted with methacholine with a rapid and complete relaxation observed at 10-4 M and 10-3
Summary
Respiratory diseases such as asthma and COPD are characterized by airway inflammation, airway obstruction and, in asthma, increased airway hyperresponsiveness (AHR) which is manifested by excessive constriction of airway smooth muscle (ASM) [1]. Β2-AR agonists mediate relaxation of airway smooth muscle through signaling of Gs protein coupled β2-adrenoceptors (GPCR) which activates the enzyme adenylyl cyclase (AC) to produce cyclic adenosine 3’,5’-monophosphate (cAMP), which in turn activates protein kinase A (PKA). Phosphorylation of myosin light chain kinase and other specific target proteins by PKA induces smooth muscle relaxation by reducing intracellular [Ca2+] concentration and decreasing Ca2+-sensitivity of the contractile elements [3]. The need to find compounds that provide therapeutic relief but act through alternative intrasignaling pathways from different classes of receptors could improve the treatment of obstructive airway diseases. In the present study we are proposing a novel potential therapeutic target
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