Leukotriene receptors as potential therapeutic targets

Abstract

Leukotrienes, a class of arachidonic acid-derived bioactive molecules, are known as mediators of allergic and inflammatory reactions and considered to be important drug targets. Although an inhibitor of leukotriene biosynthesis and antagonists of the cysteinyl leukotriene receptor are clinically used for bronchial asthma and allergic rhinitis, these medications were developed before the molecular identification of leukotriene receptors. Numerous studies using cloned leukotriene receptors and genetically engineered mice have unveiled new pathophysiological roles for leukotrienes. This Review covers the recent findings on leukotriene receptors to revisit them as new drug targets.

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…Eicosanoids are proinflammatory lipid mediators, including the prostanoid family: PG (PG12, PGF2, PGD2, and PGE2), cyclopentenone PG (15d-PGJ2, Δ12-PGJ2, PGJ2, PGC2, PGA1, and PGA2), and thromboxane A2 (TxA2); the LT family (LTC4, LTD4, LTE4, LTF4, LTD4, LTA4, and LTB4); and the eoxin family (A4, C4, D4, and E4) [100]. Eicosanoids play a key role in the initiation of the acute inflammatory process [101][102][103][104][105][106][107][108][109][110] (see Table 2).…”

Novel highly potent OXE receptor antagonists with prolonged plasma lifetimes that are converted to active metabolites in vivo in monkeys

“…Arachidonic acid metabolites formed by the 5-lipoxygenase pathway are important mediators in asthma, and drugs targeting their biosynthesis reduce disease symptoms in humans (Haeggstrom, 2018;Peters-Golden & Henderson, 2007). While the focus has principally been on LTD 4 , acting through the selective CysLT 1 receptor (Peters-Golden & Henderson, 2007;Yokomizo, Nakamura, & Shimizu, 2018), other 5-LO products may also play a role. LTB 4 , LTD 4 , and other CysLTs are only very weak chemoattractants for human eosinophils (Morita, Schroder, & Christophers, 1989;Powell, Chung, & Gravel, 1995;Sun et al, 1991), which play a major role in asthma and other allergic diseases (McBrien & Menzies-Gow, 2017).…”

Cysteinyl maresins regulate the prophlogistic lung actions of cysteinyl leukotrienes

“…The CysLTs bind specific receptors, including CysLT1, to transduce their potent bioactions. 7,8 As demonstrated recently in specific binding studies, MCTR1, MCTR2, and MCTR3 compete for specific tritiated LTD 4 binding to human recombinant CysLT1 with apparent lower affinity than LTD 4 18 and reduce LTD 4 -mediated intracellular signaling. 18 The relatively lower affinity of MCTRs to CysLT1 compared with LTD 4 suggests that MCTRs can signal through other CysLT-specific receptors, such as GPR99, an LTE 4 receptor, 25,26 and high-affinity MCTR-specific receptors that are yet to be uncovered.…”

“…[4][5][6][7] These cysteinyl leukotrienes (CysLTs) exert their bioactions by binding and activating specific receptors that transduce contraction of human airway smooth muscle and vascular permeability. 8 Selective cysteinyl leukotriene receptor 1 (CysLT1) antagonists are drugs in clinical use for asthma treatment but with surprisingly limited clinical effectiveness. 9 In view of these findings, additional regulatory mechanisms and chemical mediators are likely to be involved in the pathobiology of asthma and other diseases in which unresolved inflammation is pivotal.…”