PT  - JOURNAL ARTICLE
AU  - Montserrat Miralpeix
AU  - Carla Carcasona
AU  - Israel Ramos
AU  - Carlos Puig
AU  - Dolors Vilella
AU  - Amadeu Gavaldà
AU  - Mònica Aparici
TI  - <em>In vitro</em> pharmacological characterization of two novel dual-acting MABA compounds (LAS190792 and LAS191351)
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - 4863
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/4863.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/4863.full
SO  - Eur Respir J2014 Sep 01; 44
AB  - BackgroundThis study assessed the in vitro pharmacological profile of two novel bifunctional M3-antagonist/β2-agonist (MABA) compounds in development for chronic respiratory diseases with airflow limitation.MethodsReceptor binding and ß-adrenergic activity was assessed using CHO cell membranes expressing human M1, M2 and M3, and β1 and β2 receptors. Electrical-field stimulated (EFS) guinea pig tracheal preparations were used to assess global functional MABA potency, onset and duration of action (DoA); functional M3 potency (in the presence of propranolol) and β2 potency (in resting tone [RT] preparations) were tested. β1 activity was assessed by change in force of contraction in guinea pig left atria. Comparators were tiotropium and indacaterol.ResultsLAS191351 had human M3-receptor affinity similar to tiotropium; LAS190792 was 5-fold lower. LAS190792 was the most potent β2-agonist in inducing cAMP production and trachea relaxation (RT, IC50: 0.23 nM). Both compounds had similar or higher ß1/ß2 selectivity vs indacaterol. Global potency (IC50: LAS190792, 1.3 nM; LAS191351, 2.6 nM) was similar to tiotropium (1.2 nM) and indacaterol (0.8 nM). Functional M3 potency was greater for LAS191351 than LAS190792 (IC50: 2.8 vs 4.3 nM, respectively). Both MABAs had an onset of action faster than tiotropium; DoAs were LAS190792 206 min, LAS191351 >480 min, indacaterol 200 min and tiotropium >480 min.ConclusionLAS190792 and LAS191351 are potent and selective MABAs with different M3/β2 activity in vitro. Further studies are needed to determine duration and bronchodilator efficacy of these MABAs in humans with the aim of developing a long-acting triple therapy for asthma and COPD.