Work

A Comparison of the Molecular Pharmacological Properties of Current Short, Long, and Ultra‐Long‐Acting β2‐Agonists Used for Asthma and COPD

Year: 2025

Type: article

Abstract: 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 labeled 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 utilize 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 suggests 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) may be as important in final clinical patient outcomes as the molecular pharmacological properties of the individual β2‐agonists themselves.

Source: Pharmacology Research & Perspectives

DOI: 10.1002/prp2.70154

Authors: Richard G. W. Proudman, Jillian G. Baker

Institutions: University of Nottingham, Queen's Medical Centre, Sherwood Forest Hospitals NHS Foundation Trust, Kings Mill Hospital

Language: English

Topic: Receptor Mechanisms and Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,160