Leukotriene Receptors

Leukotrienes (LTs) exist as two distinct classes, hydroxyacids (such as LTB4), and cysteinyl leukotrienes (such as LTC4, LTD4 and LTE4). Leukotriene receptors have been classified into BLT and CysLT types to signify this basic level of selectivity, but there is also heterogeneity within both classes. Thus, there are two subtypes of both BLT, termed BLT1 and BLT2, and CysLT, termed CysLT1 and CysLT2. There may also be further subdivision of CysLT receptors, but this remains to be confirmed. The classification into types and subtypes of LT receptor was based initially on functional data, using the natural agonists and a wide range of antagonists. While LTB4 may be regarded as a selective agonist at BLT receptors, and cysteinyl LTs are selective agonists at CysLT receptors, no subtype-selective agonist has been reported for BLT1 or either CysLT receptor. Furthermore, despite the availability of a plethora of antagonists at both BLT receptors and CysLT1 receptors, no selective antagonist has yet been reported for CysLT2 receptors. The only compound reported to exhibit antagonist activity at this receptor is the non-selective CysLT antagonist, BAYu9773. The evidence for further subdivision of CysLT receptors is that responses of human and porcine pulmonary artery to cysteinyl LTs are resistant to CysLT1 and CysLT2 antagonists.

BLT1, BLT2, CysLT1 and CysLT2 receptors have now all been cloned; the first was the human BLT1 receptor in 1999 from an HL-60 cell cDNA library, and shown to be a G protein-coupled receptor that had erroneously been identified as the P2Y7 purinoceptor. Interestingly, the promoter for the BLT1 receptor was later found to lie in the open reading frame of the gene for the BLT2 receptor. The CysLT1 and the CysLT2 receptors, both cloned in 2000, again proved to be members of the G protein-coupled receptor superfamily. LT receptors may couple, albeit not exclusively, via Gi to inhibit adenylate cyclase, and Gq/11 to modulate inositol phospholipid hydrolysis and calcium mobilization.

Studies variously using agonists, antagonists and gene deletion all suggest that LTs are important pro-inflammatory mediators, although the specific actions mediated by BLT and CysLT receptors are quite distinct. BLT receptors primarily mediate chemoattraction; BLT agonists being highly potent in the recruitment of neutrophils and to a lesser extent eosinophils to sites of inflammation. Like other chemotactic agents, such as fMLP, they also appear to induce the release of lysosomal enzymes and superoxide anion. BLT agonists appear to have no direct effects on smooth muscle, and although they have been shown to elicit a contraction of airway smooth muscle in the guinea pig, this effect appears to be secondary to phospholipase C-induced mobilization of arachidonic acid from membrane phospholipids, and subsequent prostanoid generation. Despite the association between BLT receptors and the activation of inflammatory cells, disappointing clinical findings suggest that selective BLT receptor antagonists are of limited use in the treatment of asthma.

CysLT receptors mediate a range of other pro-inflammatory effects, such as constriction of airways and vascular smooth muscle, increased endothelial membrane permeability, leading to plasma exudation and edema, and an enhanced secretion of thick, viscous mucus. The cysteinyl LTs have been implicated in various inflammatory diseases, notably asthma. It is believed that the adverse effects observed with non-steroidal anti-inflammatory agents (cyclo-oxygenase inhibitors) in conditions such as asthma and inflammatory bowel disease result at least in part from an enhancement of LT release through the removal of a prostanoid-induced suppression. The development of potent, long acting, orally active CysLT receptor blocking drugs, such as zafirlukast, montelukast, and pranlukast, has provided evidence for a role of CysLT receptors in asthma; these compounds now being increasingly regarded as useful additions to the therapeutic armory in the treatment of this disease.


The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


Currently Accepted Name BLT1 BLT2 CysLT1 CysLT2
Alternate Name None None None None
Structural Information 352 aa (human) 358 aa (human) 338 aa (human) 347 aa (human)
Subtype Selective Agonists Not Known
15(S)-HETE (H1142)
LTD4 (L5011)
BAYu9773a (B9680)
Subtype Selective Antagonists U-75302
LY-255283 Montelukast (SML0101)
Zafirlukast (Z4152)
Pranlukast (P0080)
Cinalukast (C6239)
SKF 104353
ZD 3523
Not Known
Receptor Selective Agonists LTB4 (L0517)
LTB4 (L0517) LTC4
Receptor Selective Antagonists ZK 158252
CP 195543
RG 14893b
SC 53228b
ONO 4057b
RP 69698b
ZK 158252
CP 195543
BAYu9773 (B9680)
BAYu9773a (B9680)
Signal Transduction Mechanisms Gi (cAMP modulation) Gi (cAMP modulation) Gq/11 (increase IP3/DAG) Gq/11 (increase IP3/DAG)
Radioligands of Choice [3H]-LTD4
[3H]-LTB4 [3H]-LTD4
[3H]-ICI 198,615
Not Known
Tissue Expression Leukocytes Ubiquitous Leukocytes, various
bronchopulmonary tissues
Leukocytes, heart, adrenal medulla
Physiological Function Inflammation, T cell recruitment Not Known
Inflammation, contraction Endothelial function
Disease Relevance Inflammatory Not Known
Asthma, allergy Not Known




a) BAYu9773 has been reported to demonstrate partial agonist activity at recombinant CysLT2 receptors.

b) Affinity for BLT2 receptors not reported.




BAYu9773: 6(R)-(4′€™-Carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid
BAYx7195: (4S)-[4-Carboxyphenylthio]-7-[4-(4-phenoxybutoxy)-phenyl]-hept-5-(z)-enoic acid
CGS23131: 5-(3-Carboxybenzoyl)-2-((6-(4-methoxyphenyl)-5-hexenyl)oxy)benzenepropanoic acid
CGS25019C: 4-(5-[4-{Aminoiminomethyl}phenoxy]-pentoxy)-3-methoxy-N,N-bis(1-methylethyl)-benzamide-(Z)-2-butenedioate
CP-105696: (+)-1-(3S,4R)-[3-(4-Phenyl-benzyl)-4-hydroxy-chroman-7-yl] cyclopentane carboxylic acid
CP-195543: 2-[(3S,4R)-3,4-Dihydro-4-hydroxy-3-(phenylmethyl)-2H-1-benzopyran-7-yl]-4-(trifluoromethyl)benzoic acid
ICI 198,615: [1-[[2-Methoxy-4-[[(phenylsulfonyl)amino]carbonyl]phenyl]methyl]-1H-indazol-6-yl]-carbamic acid cyclopentyl ester
LY-170680 (Sulukast): 3-(((1R,2E,4Z)-1-((aS)-a-Hydroxy-m-1H-tetrazol-5-ylbenzyl)-2,4-tetradecadienyl)thio)propionic acid
LY-255283: 1-[5-Ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]ethanone
LY-293111: 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid
ONO 4057: 5-[2-(2-Carboxyethyl)-3-[6-(4-Methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid
RG 14893: 4-(2-(Methyl(2-phenethyl)amino)-2-oxoethyl)-8-(phenylmethoxy)-2-naphthalenecarboxylic acid
RP 69698: 2-[[5-Methyl-5-(1H-tetrazol-5-yl)hexyl]oxy]-4,6-diphenylpyridine
SB-209247: (E)-3-[6-[[(2,6-Dichlorophenyl)thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid
SC 53228: (+)-(S)-7-[3-[2(-Cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid
SKF 104353: 2-Hydroxy-3-carboxyethylthio-3-[2-(8-phenyloctyl)phenyl]propanoic acid
U-75302: (5S)-6-[6-[(1E,3R,5Z)-3-Hydroxy-1,5-undecadienyl]-2-pyridinyl]-1,5-hexanediol
ZD 3523: 4-[[5-[((2R)-2-Methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methylindol-3-yl]methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide
ZK 158252: 5-[2-[5-Hydroxy-5-[1-(3-phenyl-2-propynyl)cyclobutyl]-1,3-pentadienyl]cyclohexylidene]-pentanoic acid



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