Montelukast and
pranlukast are orally active
leukotriene receptor antagonists selective for the
CysLT1 receptor. Conversely, the hP2Y(1,2,4,6,11,12,13,14) receptors represent a large family of GPCRs responding to either
adenine or
uracil nucleotides, or to
sugar-
nucleotides.
Montelukast and
pranlukast were found to inhibit
nucleotide-induced
calcium mobilization in a human monocyte-macrophage like cell line,
DMSO-differentiated U937 (dU937).
Montelukast and
pranlukast inhibited the effects of
UTP with IC50 values of 7.7 and 4.3 microM, respectively, and inhibited the effects of
UDP with IC50 values of 4.5 and 1.6 microM, respectively, in an insurmountable manner. Furthermore,
ligand binding studies using [3H]
LTD4 excluded the possibility of orthosteric
nucleotide binding to the
CysLT1 receptor. dU937 cells were shown to express P2Y2, P2Y4, P2Y6, P2Y11, P2Y13 and P2Y14 receptors. Therefore, these antagonists were studied functionally in a heterologous expression system for the human P2Y receptors. In 1321N1
astrocytoma cells stably expressing human P2Y(1,2,4,6) receptors, CysLT1 antagonists inhibited both the P2Y agonist-induced activation of
phospholipase C and intracellular Ca2+ mobilization. IC50 values at P2Y1 and
P2Y6 receptors were <1 microM. In control
astrocytoma cells expressing an endogenous
M3 muscarinic receptor, 10 microM
montelukast had no effect on the
carbachol-induced rise in intracellular Ca2+. These data demonstrated that
CysLT1 receptor antagonists interact functionally with signaling pathways of P2Y receptors, and this should foster the study of possible implications for the clinical use of these compounds in
asthma or in other inflammatory conditions.