Leukotriene receptors, cysteinyl

Spinozzi, F. et al., Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes, Clin. Exp. Allergy, 34, 1876, 2004. 

Cysteinyl leukotriene receptor M201V, SNPs Tristan da Cunha, Caucasian, Loss of function (167,287-292) ... 

Fukai, H., Ogasawara, Y., Migita, O., et al. (2004) Association between a polymorphism in cysteinyl leukotriene receptor 2 on chromosome 13ql4 and atopic asthma. Pharmacogenetics. 14,683-690. 

Leukotrienes (LTA, LTB LTC, LTD, and LTE ) are synthesized from arachi-donic acid by a cascade of enzymes that include 5-lipoxygenase (5-LOX), 5-lipoxy-genase-activating protein (FLAP), and leukotriene C4 synthase (LTC synthase) (79,80). The leukotriene LTA is synthesized by 5-LOX in the first step and is an unstable precursor that is then enzymatically converted to LTB or LTC (80,81), which can subsequently be metabolized to LTD and LTE. LTC, LTD, and LTE are the components of the slow-reacting substance of anaphylaxis. These moieties, particularly LTC and LTD, are active forms of CysLTs that interact with the G protein-coupled cysteinyl leukotriene receptors (CysLtrl and CysLtr2) (70,81,82). Once engaged, the activated CysLtrs receptors stimulate the secretion of mucus and induce edema and bronchoconstriction (81). 

Hui Y, Funk CD. (2002) Cysteinyl leukotriene receptors. Biochem Pharmacol. 64, 1549-1557. 

Corrigan C, Mallett K, Ying S, et al. (2005) Expression of the cysteinyl leukotriene receptors cysLT(l) and cysLT(2) in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis. J Allergy Clin Immunol. 115, 316-322. 

Kim SH, Oh JM, Kim YS, et al. (2006) Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males. Clin Exp Allergy. 36, 433-439. 

Park JS, Chang HS, Park CS, et al. (2005) Association analysis of cysteinyl-leukotriene receptor 2 (CY SLTR2) polymorphisms with aspirin intolerance in asthmatics. Pharmacogenet Genomics. 15, 483 92. 

GPR17, GPR34, FK79 Purines Cysteinyl Leukotriene receptor ligands... 

Pharmacology Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotrine (CysLTi) receptor. 

Mechanism of Action An antiasthmatic that binds to cysteinyl leukotriene receptors, inhibiting the effects of leukof rienes on bronchial smooth muscle. Therapeutic Effect Decreases bronchoconstriction, vascular permeability, mucosal edema, and mucus production. 

It is a cysteinyl leukotriene receptor antagonist indicated for the management of persistent asthma. It has been shown to have substantial blockade of airway leukotriene receptors 24 hours after oral dosing. Montelukast appears to be a useful alternative or adjunct to inhaled corticosteroid therapy in adults and an alternative to sodium cro-moglycate in children. 

The cysteinyl leukotrienes, particularly LTC4 and LTD4, are potent bronchoconstrictors and cause increased microvascular permeability, plasma exudation, and mucus secretion in the airways. Controversies exist over whether the pattern and specificity of the leukotriene receptors differ in animal models and humans. LTC4-specific receptors have not been found in human lung tissue, whereas both high- and low-affinity LTD4 receptors are present. 

Bisgaard H. Pathophysiology of the cysteinyl leukotri-enes and effects of leukotriene receptor antagonists in asthma. Allergy. 2001 56 (suppl 66) 7—11. 

Other, recent additions to prophylaxis in asthma therapy include the leukotriene receptor antagonist montelukast. This drug is taken as a tablet and blocks the actions of cysteinyl leukotrienes in the airways. The latter are products of the lipoxygenase pathway which cause bronchoconstriction and inflammation. It is no more effective than standard corticosteroids in the prophylaxis of asthma, but there is some evidence that when given together with a steroid there maybe a beneficial additive effect. 

These block the cysteinyl leukotriene type 1 receptor, which mediates the bronchoconstriction and anti-inflammatory actions of leukotrienes the latter do not seem to be reduced by corticosteroids. Therefore leukotriene receptor antagonists are used to complement steroids when the latter do not effectively control symptoms. 

The leukotriene receptor antagonists are antagonists of cysteinyl leukotrienes at CysLTi receptors and include zafirlukast, montelukast, and pranlukast. 

Churg-Strauss syndrome has been reported in an 18-year-old woman taking cysteinyl leukotriene receptor antagonists and oral rokitamicin 400 mg bd for 10 days (2). 

Taylor, I.K., O Shaughnessy, K.M., Fuller, R.W. and Dollery, C.T. (1991). Effect of cysteinyl-leukotriene receptor antagonist ICl 204.219 on alletgen-induced bronchoconstriction and airway hyperreactivity in atopic subjects [see comments]. Lancet 337, 690-694. 

Corenne. I. et ai (1996) Cysteinyl leukotriene receptors in the human lung ... 

Rovail. G.E. er al. (1997) More on the classification of cysteinyl leukotriene receptors. Trends Pharmacol. Sci., 18.148-149. 

As a result of their prolonged and potent bronchoconstrictor actions, a role for the cysteinyl leukotrienes (viz. C4, D4, and E4) in the genesis of asthmatic bronchospasm was suspected and is now well established. Consistent with this, inhibition of 5-LO using zileuton has been shown to relieve mild to moderate asthma [70]. Compared to their cysteinyl leukotriene receptor antagonist brethren (vide infra), 5-LO inhibitors are in their early stages of development. Currently, zileuton is the only 5-LO inhibitor available and is administered as an oral formulation. It is likely that more inhalable 5-LO inhibitors will available in the future. 

Histamine receptor H3 (HRH3) Cysteinyl leukotriene receptor 1 (CYSLTR1) G300S... 

Xql3-q21 Cysteinyl leukotriene receptor 2 (CYSLTR2) M201V, SNPs... 

---