A comparison of the molecular pharmacological properties of current short, long and ultra-long-acting β2-agonists used for asthma and COPD

Proudman, Richard G W; Baker, Jillian G

Abstract

β-agonists have been used in asthma for 120 years. There are two recent changes: ultra-long-acting agonists for COPD and new asthma guidelines recommending formoterol/ICS inhalers phasing out short-acting salbutamol inhalers. Few studies directly compare the molecular pharmacological properties of short (salbutamol, terbutaline, fenoterol), long (formoterol, salmeterol) and ultra-long-acting (indacaterol, olodaterol, vilanterol) β2-agonists. Here, the in vitro molecular pharmacological properties of affinity, selectivity, intrinsic efficacy and duration of β2-agonists at human β2 and β1-adrenoceptors and the 4 β2-polymorphisms stably expressed in CHO cells were directly compared using radioligand binding and functional studies. Whilst short-acting drugs were similar, there was huge variation and complete overlap in the molecular pharmacological properties of drugs labelled as long and ultra-long-acting β2-agonists. Salmeterol and vilanterol were highly β2-selective (>1000-fold) whereas indacaterol was similar to salbutamol (40-fold). Formoterol and indacaterol were the most efficacious, whereas salmeterol had the longest duration of binding. Salmeterol and vilanterol utilise a β2-specific exosite (β2-H296-K305) for high affinity and selectivity (that does not affect intrinsic efficacy or duration) whilst the β2-selectivity of formoterol and olodaterol resides elsewhere. Duration of binding closely correlated with lipophilicity. β2-polymorphisms had no substantial effect on β2-agonist properties. Comparison with other β-ligands, suggest that affinity and duration could both be improved further. However, given the very wide range of molecular pharmacological properties of β-agonists that are clinically effective and widely-used, non-pharmacological properties (physiochemical, patient factors, devices and combination inhaler availability) maybe as important in final clinical patient outcomes as the molecular pharmacological properties of the individual β2-agonist themselves.

Citation

Proudman, R. G. W., & Baker, J. G. (in press). A comparison of the molecular pharmacological properties of current short, long and ultra-long-acting β2-agonists used for asthma and COPD. Pharmacology Research and Perspectives, https://doi.org/10.22541/au.174560615.57789698/v1

• Journal Article Type: Article
• Acceptance Date: Jul 2, 2025
• Deposit Date: Jul 3, 2025
• Journal: Pharmacology Research and Perspectives
• Electronic ISSN: 2052-1707
• Publisher: Wiley Open Access
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.22541/au.174560615.57789698/v1
• Public URL: https://nottingham-repository.worktribe.com/output/48350710