The interaction of azelastine with human lung histamine H1, beta, and muscarinic receptor-binding sites

Azelastine has previously been demonstrated to inhibit histamine release, to antagonize histamine-mediated responses, and to be a bronchodilator. To determine the mechanism by which azelastine has antihistaminic and bronchodilatory actions, we studied its interaction with relevant human lung receptors. We performed competitive radioligand binding assays and determined the affinity of azelastine for [3H]pyrilamine (histamine H1), [125I]pindolol (beta), and [3H]quinuclidinyl benzilate (muscarinic) binding sites. Azelastine had a relatively high affinity for histamine H1 receptors with IC50 values consistently as low or lower than values measured for other antihistamines. In contrast, azelastine had a very low affinity for both beta-receptors and muscarinic receptors with IC50 values greater than 2 logs greater than those determined for beta-agonists and muscarinic antagonists, respectively. Thus, bronchodilatory activity of azelastine does not appear to result from either beta-agonist or muscarinic-antagonist properties. Azelastine does, however, have the ability to inhibit the release of histamine and to bind to histamine H1 receptors, thereby effectively antagonizing histamine H1 receptor-mediated responses in the lung. These characteristics make azelastine a potentially very useful drug to treat allergic responses in the respiratory tract.