Endothelin Receptors

Endothelins are a family of vasoactive peptides that were discovered in a search for the identity of a vasoconstricting factor known to exist in the media from cultured endothelial cells. The first member of this family, endothelin-1 or ET-1, was revealed in a seminal Nature article published in March, 1988. Subsequently, ET-2, ET-3 and several snake venom toxins, called sarafotoxins, were identified as members of a structurally defined family of bicyclic 21 amino acid peptides.

The mammalian peptides, ET-1 and ET-3, are produced by a wide range of tissues and cells. ET-1 is the primary isoform circulating in plasma. ET-3 has been found in high levels in brain. ET-2 may be more selectively produced in the kidney and intestine, but its functional significance remains poorly defined. The endothelins are all coded from separate genes and the gene products require proteolytic processing to produce mature endothelins. A number of endothelin converting enzymes (ECE) have been identified that may be important in the final proteolytic activating step.

The endothelins function through their interaction with G protein-coupled receptors. To date, two subtypes have been cloned from mammalian cells, ETA and ETB. The ETA receptors have a much greater affinity for ET-1 over ET-3 and are expressed abundantly in vascular smooth muscle and stromal tissues. In humans and animals, in vivo and in vitro studies with selective antagonists have revealed that the vasoconstrictor and proliferative effects of ET-1 are primarily mediated by the ETA receptor. The ETB receptor binds both ET-1 and ET-3 with nearly equal affinity and is expressed abundantly on endothelial cells and epithelial tissues. While the ETB receptor can mediate a vasoconstrictor response, its physiological role appears to be two-fold: i) mediation of ET-1-induced nitric oxide release from endothelial cells and an accompanying vasodilation response, and ii) clearance of ET peptides from the circulation. These conclusions are supported by studies with ETB-selective antagonists that block the transient vasodilation response observed upon bolus intravenous administration of ET-1 or studies showing that hypertension is associated with chronic administration of ETB antagonists, and the marked increase in plasma endothelin levels upon ETB-selective or non-selective receptor blockade, but not ETA-selective blockade. In addition to their vasoactive properties, these receptors are involved in regulation of cell proliferation. Gene disruption studies indicate that both receptor subtypes and, ET-1 and ET-3 peptides, play important roles in embryologic development.

Perhaps the most interesting area of ET research to emerge in the last few years relates to the potential role of ET in the regulation of bone growth. ET-1, via ETA receptors, has been found to stimulate osteoblast activity resulting in abundant and disorganized new bone characteristic of osteoblastic metastases. The connection between tumors that produce excessive ET-1 and metastatic bone disease is intriguing and has led to an interest in utilizing ET receptor antagonists to treat prostate cancer.

Therapeutic interest in blocking the endothelin system has been high, leading to the discovery of a large number of peptidic and non-peptide receptor antagonists. These antagonists may have utility in a number of cardiovascular diseases, including congestive heart failure, pulmonary hypertension, stroke, kidney failure, hypertension, angioplasty-induced restenosis, and a variety of non-cardiovascular conditions, such as asthma, chronic obstructive pulmonary disease, pain and cancer.

 

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

 

Currently Accepted Name ETA
ETB
Structural Information 427 aa (human) 442 aa (human)
Preferred Endogenous Peptides ET-1 (E7764) = ET-2 (E9012) >> ET-3 (E9137) ET-1 (E7764) = ET-2 (E9012) = ET-3 (E9137)
Subtype Selective Agonists Not Known
[Ala1,3,11,15]-ET-1 (E6877)
Sarafotoxin S6c (S6545)
IRL-1620 (SCP0135)
BQ-3020 (SCP0138)
Subtype Selective Antagonistsa A-127722b
A-147627 (ABT-627, Atrasentan)
A-216546
BQ-123 (B150)
BQ-610
FR 139317
Lu-135252 (Darusentan)
PD 151,242 (P208)
PD 156,707
TBC-11251 (Sitaxsentan) (PZ0203)
A-192621
BQ-788 (B157)
RES-701-1 (R4027)
Ro 46-8443
Non-Selective Antagonists A-182086
Ro-61-6612 (Tezosentan)
SB-209670
SB-217242 (Enrasentan)
PD 142,893 (SCP0134)
PD 145,065
Ro 47-0203 (Bosentan)
A-182086
Ro-61-6612 (Tezosentan)
SB-209670
SB-217242 (Enrasentan)
PD 142,893 (SCP0134)
PD 145,065
Ro 47-0203 (Bosentan)
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG)c Gq/11 (increase IP3/DAG)c
Radioligands of Choice [125I]-ET-1
[3H]-BQ-123
[125I]-ET-1
[125I]-ET-3
Tissue Expression Widespread: higher in vascular and stromal cells Widespread: higher in endothelial and epithelial cells
Physiological Function Vasoconstriction
Proliferation
ET-1 clearance
Disease Relevance Cardiovascular
Renal
Cancer
Not Known

 

Footnotes

a) “Subtype Selective Antagonists” means > 500-fold.

b) A-127722 is the racemic version of A-147627 (ABT-627, Atrasentan).

c) Some evidence exists to suggest that endothelin receptors may signal through other signal transduction mechanisms.

 

Abbreviations

A-127722: trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
A-147627 (ABT-627): (2R,3R,4S)-(+)-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
A-186086: (2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)1-(2-(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid
A-192621: (2R,3R,4S)-2-(4-Propoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2,6-diethylphenylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid
A-216546: [2S-(2,2-Dimethylpentyl)-4S-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3R-carboxylic acid
BQ-123: cyclo (D-α-Aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl)
BQ-610: N-[1-Formyl-N-[N-[(hexahydro-1H-azepin-1-yl)carbonyl]-L-leucyl]-D-tryptophyl]-D-tryptophan
BQ-788: N-[N-[N-[(2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine
BQ-3020: N-Acetyl-[Ala11,15]-Endothelin-1(6-21)
ET-1: Endothelin-1
ET-2: Endothelin-2
ET-3: Endothelin-3
FR 139317: (R)2-[(R)-2-[(S)-2-[[1-(Hexahydro-1H-azepinyl)]carbonyl]amino-4-propionyl]amino-3-(2-pyridyl)propionic acid
IRL 1620: N-Suc-[Glu9,Ala11,15]-Endothelin-1(8-21)
Lu 135252: (+)-(S)-2-(4,6-Dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid
PD 142,893: N-Acetyl-β-Phenyl-D-Phe-Leu-Asp-Ile-Ile-Trp
PD 145,065: N-Acetyl-α-[10,11-Dihydro-5H-dibenzo[a,d]cycloheptadien-5-yl]-D-Gly-Leu-Asp-Ile-Ile-Trp
PD 151,242: N-[N-[N-[(Hexahydro-1H-azepin-1-yl)carbonyl]-L-leucyl]-1-methyl-D-tryptophyl]-D-tyrosine
PD 156,707: Sodium 2-benzo[1,3]dioxol-5-yl-4-(4-methoxyphenyl)-4-oxo-3-(3,4,5-trimethoxybenzyl)-but-2-enoate
RES-701-1: cyclic (Gly1-Asp9) (Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp-Trp-Phe-Phe-Asn-Tyr-Tyr-Trp)
Ro 46-8443: N-[6-[(2R)-2,3-Dihydroxypropoxy]-5-(2-methoxyphenoxy)-2-(4-methoxyphenyl)-4-pyrimidinyl]-4-(1,1-dimethylethyl)-benzenesulfonamide
Ro 47-0203: 4-Tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxyphenoxy)-2,2’-bipyrimidin-4-yl]-benzenesulfonamide
Ro 61-0612: 5-Isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide
SB-209670: (±)-(1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid
SB-217242: 1-(1,3-Benzodioxol-5-yl)-2,3-dihydro-3-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-5-propoxy-,-1H-indene-2-carboxylic acid
TBC-11251: N-(4-Chloro-3-methyl-5-isoazolyl)-2-[(6-methyl-1,3-benzodioxol-5-yl)acetyl]-3-thiophenesulfonamide

 

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References