Lipoxygenase receptors

Most of the drugs such as epinephrine and albuterol used to treat asthma attacks are bronchodilators—substances that expand the bronchial passages Newer drugs are designed to either inhibit the enzyme 5 lipoxygenase which acts on arachidomc acid m the first stage of leukotriene biosynthesis or to block leukotriene receptors... 

Lipoxygenase AVNTR polymorphism in 100 bp upstream from the ATG start codon is associated with transcription efficiency. Differences in response to 5-lipoxygenase inhibitors and leucotriene receptor antagonists. 

In a study looking at oxygenated metabolites of AEA and their interaction with the cannabinoid system, a series of hydroxylated alkyl chains was prepared using different lipoxygenases as biocatalysts [152-154]. Of the seven AEA derivatives prepared, only the 5R-hydroxy (208), 125 -hydroxy (209) and 155 -hydroxy (210) derivatives had any affinity for the CBi receptor. Interestingly, the IdV-hydroxy compound (211) that was inactive at the CBi receptor displayed some affinity for the CB2 receptor [152] (see Table 6.18). 

Hampson, AJ, Hill WA, Zan Phillips M, Makriyannis A, Leung E, Eglen, RM, Bornheim LM. Anandamide hydroxylation by brain lipoxygenase metabolite structures and potencies at the cannabinoid receptor. Biophys. Biochim. Acta 1995 1259 173-179. 

Carlberg, C. Wiesenberg, I. (1995). The orphan receptor family RZR/ROR, melatonin and 5-lipoxygenase an unexpected relationship. J. Pineal Res. 18, 171-8. 

Leprosy, chemotherapy, 20 (1983) 1 Ligand-receptor binding, 23 (1986) 41 Linear free energy, 10 (1974) 205 5-Lipoxygenase inhibitors and their antiinflammatory activities, 29 (1992) 1 Literature of medicinal chemistry, 6 (1969) 66 Lithium, medicinal use of, 11 (1975) 193 Local anaesthetics, 3 (1963) 332 Lonidamine and related compounds, 21 (1984)111... 

CysLTs) are proinflammatory molecules synthesized primarily by basophils, neutrophils, and mast cells and are potent mediators of airway inflammation and bronchoconstriction (77,78). There are two classifications of drugs in this category that can regulate the effects of CysLTs inhibitors of the 5-lipoxygenase enzyme, such as zileuton, and CysLT receptor antagonists, such as montelukast and zafirlukast. 

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). 

The biological actions of the cysteinyl leukotrienes are mediated via stimulation of CysLTi receptors. Montelukast and zafirlukast are competitive antagonists of these receptors. In contrast, zileuton suppresses synthesis of the leukotrienes by inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of arachidonic acid to the leukotrienes. Zileuton also blocks the production of leukotriene B4, another arachidonic acid metabolite with proinfiammatory activity. The CysLTi-receptor antagonists alter neither the production nor the actions of leukotriene B4. 

Zileuton (8.81) is an inhibitor of 5-lipoxygenase montelukast (8.82) and zafirlukast (8.83) are inhibitors of the leukotriene LTD4 receptor. All of these agents have demonstrated efficacy in the treatment of asthma, a common chronic inflammatory disease of the airways. 

The fatty acid-like leukotrienes derived from the addition of glutathione to products of the lipoxygenase branch of the arachidonic cascade are closely associated with manifestations of asthma. Many compounds designed to antagonize leukotrienes at the receptor level incorporate long alkyl chains to mimic the leukotrienes backbone in addition to the sulfur-containing moieties that stand in for glutathione. The reaction... 

Some polyphenols inhibit platelet aggregation reducing the risk of thrombosis [171-173]. This effect may be due to a series of interaction of flavonoids in different biochemical pathways, such as by inhibition of cyclooxygenase and lipoxygenase, that are involved in the arachidonic acid metabolism in the platelets, or by inhibition of the formation of tromboxane and of the receptor function of the same [173-176]. Regular consumption of wine, tea and chocolate has been associated to the reduction of platelet aggregation, cardio-vascular diseases and thrombosis [171,177-179]. 

Figure 2 Known second-messenger pathways that modulate capsaicin or VRs. GPCR, G protein-coupled receptors PLA2, phospholipase A2 AC, adenylate cyclase IP3, inositoltriphosphate DAC diacylglycerol LM, lipoxygenase metabolites AA, arachidonic acid ANA, anandamide PG, prostaglandins Gq/11, Gq/j, Gs, trimeric G-proteins (adapted from Premkumar, 2001)...

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