Leukotriene receptor antagonists – novel mechanisms of action
All clinically available LTRAs (montelukast, zafirlukast and pranlukast)
act on the cysteinyl leukotriene type 1 receptor
(CysLT1) and by competitive antagonism at this receptor
are believed to be responsible for the control of airway inflammation,
bronchoconstriction, and remodeling.46-48 However,
anti-inflammatory activity of LTRAs independent of
CysLT1 antagonism has been suggested. LTRAs reduced the
eosinophil protease activity,49 and inhibited
TNFα-50, or UDP-mediated51,52cytokine expression, as well as NF-κB activation in human
mononuclear53 or epithelial cells54through processes that appear to be distinct from CysLT1antagonism. Although, mechanisms of these
non-CysLT1-related LTRA activities are not fully
understood, concentration dependent inhibition of distinct receptors
such as P2Y1, P2Y2, P2Y6 and GPR17 by LTRAs have been
reported,51,52,55 suggesting, at least for P2Y
receptor, a non-competitive mechanism of action. Interestingly, it was
also shown that LTRAs may have a potent inhibitory effect on 5-LOX
activity (i.e. LT production)52,56 and transport of
LTs by the multidrug resistance protein ABCC4,57suggesting a much broader mechanism of action for these drugs than
previously suspected. Indeed, non–CysLT1-related
mechanisms of LTRA might represent another level of variability in the
response to treatment in patients with asthma and allergy. Some of these
activities may be compound-specific or may depend on drug concentration
(most non-CysLT1-related effects required micromolar
drug concentrations51-53 in contrast to nanomolar
levels needed for CysLT1antagonism58-60) or may depend on the presence of a
particular inflammatory pathway in patients with asthma (allergy), and
therefore, clinically significant effects of treatment may be observed
in some, but not all, treated patients. It should be emphasized that
initial clinical interventional studies of montelukast in asthma used
doses up to 200 mg a day61,62 showing greater lung
function improvement than in subsequent studies using recommended dose
of 10 mg,63 suggesting that higher doses of currently
known LTRAs or new compounds derived from this class of drugs may
represent a novel strategy for finding more efficient therapy. The
demonstration that the bronchoconstrictive actions of
LTE4 in asthma are solely mediated by the
CysLT1 receptor further supports that effects on other
targets than the CysLT receptors may take place64