Definition

Endothelin receptor antagonists, by blocking the vasoconstrictor and cardiotonic effects of ET-1, produce vasodilation and cardiac inhibition. Endothelin receptor antagonists have been shown to decrease mortality and improve themodynamics in experimental models of heart failure ¹.

Related Peptides

Novel cyclic pentapeptides, WS7338A, B, C and D [cyclo-(AAl -AA2-D-Trp-D-Glu-Ala)] were isolated as ET-receptor antagonists from the culture broth of Sfreptomyces sp. No. 7338 ².

Discovery

Based on conformational analysis, the minimum structural requirements for binding affinity was defined by Neya et al., and a series of acylated tripeptides with ET-A receptor binding affinity were synthesized. Through extensive chemical modification of the lead tripeptide, a potent and selective ETA receptor antagonist FR139317 was discovered. Further modification of this series of tripeptide ET antagonists has led to the discovery of a highly potent and selective ET-B receptor antagonist FR164343 ².

Structural Characteristics

Cyclic pentapeptide endothelin receptor antagonists:

Through extensive modification of the cyclic pentapeptide 2 on the basis of its conformation analysis a series of tripeptide ET receptor antagonists with ETA and ETB subtype-selectivity were discovered. Further in vivo characterization demonstrated that FR139317 is a highly potent and selective ET-A receptor antagonist, whereas FR164343 is a highly potent and selective ET-B receptor antagonist. It may be concluded that FR139317 and FR164343 are useful pharma- cological agents for investigating the pathophysiological roles of the ET system ².

Mode of Action

ET-receptor antagonists are designed such that they have very high binding affinities to endothelin receptors (ET-A and ET-B). Therefore these antagonists mediate their action by blocking the ET receptor binding sites ².

Functions

ET-receptor antagonists have recently been proposed as an alternative to traditional therapies for pulmonary arterial hypertension ³. ET-receptor antagonists might be useful to treat myocardial ischemia. It is possible that during chronic therapy, inhibition of the proliferative effects of ET may be beneficial for structural changes. Hence, long-term studies with ET-receptor antagonists in coronary artery disease are necessary to determine their clinical potential ⁴. Significant hemodynamic and neurohumoral benefits were observed in patients with severe heart failure receiving the selective endothelin antagonist ⁵.

References

1. Book: Cardiovascular Physiology Concepts by Klabunde RE.
2. Neya M (1997). Discovery of endothelin antagonists. Pure & Appl Chem., 69(3):441-446.
3. Liu C, Chen J, Gao Y, Deng B, Liu K (2008). Endothelin receptor antagonists for pulmonary arterial hypertension. Database of Systematic Reviews, 4:1858-1865.
4. Wenzel RR, Fleisch M, Shaw S, Noll G, Kaufmann U, Schmitt R, Jones CR, Clozel M, Meier B, Lüscher TF (1998). Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease. Circulation, 98(21):2235-2240.
5. Bergler-Klein J, Pacher R, Berger R, Bojic, A, Stanek B (2004). Neurohumoral and hemodynamic effects of the selective endothelin antagonist darusentan in advanced chronic heart failure. J Heart Lung Transplant., 23(1):20-27.