Site-Directed Mutagenesis in the Investigation of β-Adrenoreceptor Exosite

β(2)-adrenergic receptor agonists (β-agonists) are first-line agents for the treatment of acute bronchospasm. These drugs achieve bronchodilation primarily via activation of β(2)-adrenergic receptors (β(2)AR) located on airway smooth muscle cells. In addition, β-agonists may alleviate bronchospasm, and protect against airway hyperresponsiveness, by interacting with β(2)AR expressed on other lung cells, resulting in such diverse actions as alterations in ion permeability, changes in mucocilliary beat frequency, and so on (1). Most β-agonists in clinical use are structural derivatives of the endogenous β(2)AR agonist, adrenaline, including substituted catecholamines, such as isoprenaline and isoetharine; resourcinols, such as metaproterenol, fenoterol, and terbutaline; and saligenins, such as salbutamol and salmeterol. Of these, salmeterol, a highly lipophilic derivative of the partial agonist, salbutamol, represents the latest long-acting generation of β-agonists, with a duration of activity in excess of 24 h (2).