Endothelin Receptors
The endothelin family consists of highly potent vasoconstrictive peptides. Three endogenous isoforms are known to exist - ET-1, ET-2 and ET-3. Due to their physiological role as vasoactive peptides, endothelins have been linked to certain cardiac, vascular and renal diseases; endothelin antagonists may therefore play an important role in the treatment of these conditions. Two distinct endothelin receptors have so far been cloned in mammals, classified as ETA and ETB receptors.
Endothelin receptors are widely expressed in all tissues. They are also localized to non-vascular structures including epithelial cells, glia and neurons. The principal physiological role of endothelin receptors is the maintenance of vascular tone. They also have comitogenic activity, potentiating the effects of other growth factors such as PDGF.
Endothelin Receptor Data
| Receptor Subtype | ETA Receptors | ETB Receptors |
|---|---|---|
| Transduction Mechanism | 7-TM, ↑ PI turnover → ↑ Ca2+i.c., ↑ Ca2+ influx | 7-TM, ↑ PI turnover → ↑ Ca2+i.c., ↑ Ca2+ influx |
| Primary Locations | Vascular smooth muscle | Vascular endothelial cells |
| Tissue Functions | Vasoconstriction, positive ionotrope, cell proliferation | Vasodilatation, bronchoconstriction, vasoconstriction, cell proliferation |
| Endogenous Ligand Potency | ET-1 = ET-2 > ET-3 | ET-1 = ET-2 = ET-3 |
| Key Compounds | Ki Values (nM) |
|---|
| Selective ETB Agonists |
IRL-1620 (1196) Sarafotoxin S6c (1175) BQ-3020 (1189) [Ala1,3,11,15]-Endothelin (1197) |
1190 2800 970 2200* |
0.016 0.29 0.18 0.33* |
| ETA Antagonists |
BQ-123 (1188) FR 139317 (1210) BMS 182874 (1441) Sulfisoxazole (0731) CI 1020 (2942) |
1.4 1 48 600* 0.3* |
1500 7300 > 50000 2200* 480* |
* IC50 values
References
Davenport (2000) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol.Rev. 54 219. Takai et al (1992) A potent and specific agonist, Suc-[Glu9,Ala11,15]-endothelin-1(8-21), IRL 1620, for the ETB receptor. Biochem.Biophys.Res.Comm. 184 953. Williams et al (1993) Characterization of cloned human endothelin receptors. Life Sci. 53 407. Ihara et al (1995) [3H]-BQ-123, a highly specific and reversible radioligand for the endothelin ETA receptor subtype. Eur.J.Pharmacol. 274 1. Reynolds et al (1995) Pharmacological differences between rat and human endothelin B receptors. Biochem.Biophys.Res.Comm. 209 506. Nakamichi et al (1992) Different distribution of endothelin receptor subtypes in pulmonary tissues revealed by the novel selective ligands BQ-123 and [Ala1,3,11,15]ET-1. Biochem.Biophys.Res.Comm. 182 144. Makatani et al (2000) Effect of a novel bifunctional endothelin receptor antagonist, IRL 3630A, on guinea pig respiratory mechanics. Eur.J.Pharmacol. 406 139. Aramori et al (1993) Subtype selectivity of a novel endothelin antagonist, FR 139317, for the two endothelin receptors in transfected Chinese hamster ovary cells. Mol.Pharmacol. 43 127. Webb et al (1995) BMS-182874 is a selective, nonpeptide endothelin ETA receptor antagonist. J.Pharmacol.Exp.Ther. 272 1124. Chan et al (1994) Identification of a new class of ETA selective endothelin antagonists by pharmacophore screening. Biochem.Biophys.Res.Comm. 201 228.