PHARMACOLOGY OF LEUKOTRIENE RECEPTOR ANTAGONISTS

Preclinical pharmacological studies have demonstrated that cysLT(1) re ceptor antagonists, such as zafirlukast, montelukast, and pobilukast, are potent and selective antagonists of cysteinyl leukotriene (cysLT) activity. In vitro, these agents compete with [H-3]LTD4 for binding to cysLT(1) receptors present on guinea pig and human lung cell membrane s, Both zafirlukast and montelukast have affinities that are approxima tely two times greater than that of the natural ligand, LTD4. These ag ents block LTD4- and LTE4-induced contractions of isolated guinea pig trachea, but do not antagonize LTC4-induced contractions, which are pu tatively mediated by a different LT receptor, cysLT(2). The cysLT(2) r eceptor, however, has not yet been found in human airway smooth muscle . In animal models, these drugs inhibit LTD4-, LTE4-, and antigen-indu ced bronchoconstriction, reduce inflammatory markers in models of pulm onary inflammation, and inhibit antigen-induced late-phase bronchocons triction. This preclinical profile suggests that cysLT(1) receptor ant agonists may be useful in treating inflammatory conditions of the resp iratory system, such as asthma and allergic rhinitis.