Site-Directed Mutagenesis in the Investigation of -Adrenoreceptor Exosite

β₂ -adrenergic receptor agonists (β-agonists) are first-line agents for the treatment of acute bronchospasm. These drugs achieve bronchodilation primarily via activation of β₂ -adrenergic receptors (β₂ AR) located on airway smooth muscle cells. In addition, β-agonists may alleviate bronchospasm, and protect against airway hyperresponsiveness, by interacting with β₂ 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 β₂ 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 ).