BAY u9773, a novel antagonist of cysteinyl-leukotrienes with activity against two receptor subtypes

Tudhope, Stephen R.; Cuthbert, Nigel J.; Abram, Trevor S.; Jennings, Michael A.; Maxey, Robert; Thompson, Angela; Norman, Peter; Gardiner, P.J.

doi:10.1016/0014-2999(94)00485-4

Cited by 78 publications

(39 citation statements)

References 19 publications

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“…We can therefore speculate that the same receptor exists in human lung coupled to a relaxation effect, probably mediated through stimulation of endothelial nitric-oxide synthase. BAY u9773 was also reported to contract various tissue preparations from guinea pig (Tudhope et al, 1994;Wikström Jonsson et al, 1998). It must be emphasized, however, that the molecular targets of BAY u9773 in this species might not be identical to the CysLT receptors found in the human lung (Gorenne et al, 1996).…”

Section: Discussionmentioning

confidence: 91%

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Molecular Cloning and Characterization of a Second Human Cysteinyl Leukotriene Receptor: Discovery of a Subtype Selective Agonist

et al. 2000

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Section: Discussionmentioning

confidence: 91%

“…BAY u9773 has been a useful tool to define CysLT 2 receptors pharmacologically. It has been shown to inhibit physiological responses insensitive to CysLT 1 antagonists in several species including man (Labat et al, 1992;Tudhope et al, 1994;Bä ck et al, 1996), thus allowing the detection of the CysLT 2 sites.…”

Section: Discussionmentioning

confidence: 99%

Molecular Cloning and Characterization of a Second Human Cysteinyl Leukotriene Receptor: Discovery of a Subtype Selective Agonist

et al. 2000

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“…One interpretation is that there may be a CysLT 1 receptor subtype. In addition, Tudhope et al (1994) observed a residual contraction in the guinea pig 216 NOMENCLATURE FOR LEUKOTRIENE AND LIPOXIN RECEPTORS lung strip subsequent to CysLT 1 /CysLT 2 antagonism by BAY u9773. Recently, Bä ck et al (2000a,b) have reported that the contractions to LTC 4 in porcine and human pulmonary arteries were not antagonized by either MK-571 or BAY u9773, data which further suggest the presence of another CysLT receptor responsible for the LTC 4 -induced contractions.…”

Section: Evidence For Additional Cyslt Receptor Subtypesmentioning

confidence: 93%

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

et al. 2003

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“…A third CYS-LTR, CYSLTR3, not antagonised by any current antagonists has been suggested (101). Based on relatedness to the CYSLTRs and P2Y families, this could be the dualreceptor GPR17 (102).…”

Section: Cyslt Receptorsmentioning

confidence: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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Leukotrienes (LT) are a family of potent eicosanoid lipid mediators with central importance in disease processes such as inflammation and proliferation most notably observed in allergic conditions like asthma (1). There are two general classes of LT according to the presence of a cysteine residue in their amino acid chain: the cysteinyl leukotrienes (CysLTs) including LTC 4 , LTD 4 and LTE 4 and the dihydroxyleukotriene LTB 4 (2). The 5-lipoxygenase pathwayLeukotrienes are produced in a multi-step enzyme pathway called the 5-lipoxygenase (5-LO) pathway, which is active in leucocytes such as neutrophils, eosinophils, mast cells and monocytes (Fig. 1). Arachidonic acid is the precursor for LT synthesis and is hydrolysed from the plasma membrane by cytosolic phospholipase A 2 (and other isoforms) (3, 4) in a calcium-dependent process (5). Upon activation, the rate-limiting enzyme 5-LO oxygenates first free arachidonic acid into the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is then either hydrolysed to 5-hydroxyeicosatetraenoic acid (5-HETE) or transformed into the unstable epoxide leukotriene A 4 (LTA 4 ) by forming a conjugated triene system through dehydration (6). 5-LO translocates from either the nucleus (in macrophages) or cyotosol (in neutrophils) to the nuclear envelope in response to cell activation (7,8). This movement occurs as 5-LO is dependent on a 5-LO activating protein (FLAP) for its function. FLAP remains associated with the nuclear membrane (9) and acts as a Ôtransfer proteinÕ presenting arachidonic acid to 5-LO, a system which allows the favourable conversion of 5-HPETE to LTA 4 compared to 5-HETE (10). Both 5-LO and FLAP are expressed in cells of myeloid lineage (11) restricting the pathway to these cell types. LTA 4 can be further metabolised to the cysteinyl leukotrienes (CysLTs) or LTB 4 . The specific glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) conjugates LTA 4 to form LTC 4 which can then be rapidly converted to LTD 4 by a gammaglutamyl transpeptidase and to LTE 4 by a dipeptidase once exported out the cell by membrane transport proteins such as multi-drug related protein 1 (MRP1) (12-15). A specific zinc metallohydrolase, LTA 4 hydrolase (LTA 4 H) is responsible for the conversion of LTA 4 to LTB 4 (16). CysLTs and LTB 4 act on different G-protein coupled receptors (GPCRs). Each bind to at least two different receptors: CysLTs to CYSLTR1 and CYSLTR2 and LTB 4 to LTB 4 R1 and LTB 4 R2 (or BLT1 and BLT2) (17).Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC 4 , LTD 4 and, LTE 4 ) and the dihydroxy leukotriene LTB 4 are generated by a series of enzymes/ proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotr...

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BAY u9773, a novel antagonist of cysteinyl-leukotrienes with activity against two receptor subtypes

Cited by 78 publications

References 19 publications

Molecular Cloning and Characterization of a Second Human Cysteinyl Leukotriene Receptor: Discovery of a Subtype Selective Agonist

Molecular Cloning and Characterization of a Second Human Cysteinyl Leukotriene Receptor: Discovery of a Subtype Selective Agonist

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

Leukotriene pathway genetics and pharmacogenetics in allergy

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