N-Methylleukotriene C4

Differential Signaling of Cysteinyl Leukotrienes and the Cysteinyl Leukotriene Receptor 2 Agonist N-Methyl-Leukotriene C4

Yan, Dong, et al. Molecular Pharmacology, 2011, 79(2), 270-278.

This work demonstrates in vitro and in vivo that N-methyl-leukotriene C4 (NMLTC4), a metabolically stable LTC4 mimetic, is a potent and selective CysLT2 receptor agonist. Furthermore, it can be used as a selective tool together with the selective CysLT receptor antagonist HAMI3379 to identify some of the physiological and pathophysiological roles played by CysLT receptors in the tissues and cells in which they reside.
Research methods and results
· Two expression systems were employed to assess the functional activity of NMLTC4 at human and/or mouse CysLT1 and CysLT2 receptors. The aequorin cell-based assay for calcium-coupled GPCRs revealed that NMLTC4 displayed nearly equal potency to LTC4 at CysLT2 receptors, but demonstrated lower efficacy at CysLT1 receptors.
· In the β-galactosidase-β-arrestin complementation assay, the human CysLT2 receptor successfully engaged β-arrestin-2, with NMLTC4 showing slightly greater potency in promoting β-arrestin-2 binding compared to cysteinyl leukotrienes (cysLTs).
· Additionally, LTE4 showed minimal activity in this assay, contrasting with its weak partial agonist behavior observed in the aequorin system. In a vascular leakage assay, NMLTC4 proved to be potent and effective in mice with overexpression of the hCysLT2 receptor in the endothelium; however, this response was abolished in mice lacking the CysLT2 receptor.