An endothelin receptor (ETA) antagonist isolated from Streptomyces misakiensis

Ihara, Masaki; Fukuroda, Takahiro; Saeki, Toshihiko; Nishikibe, Masaru; Kojiri, Katsuhisa; Suda, Hiroyuki; Yano, Mitsuo

doi:10.1016/0006-291x(91)91789-f

Cited by 188 publications

(62 citation statements)

References 19 publications

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“…However, a distinction between ETA-and ETa-mediated functions still remains unestablished, mainly because of the lack of antagonists specific for each subtype of the receptor. Several specific ,-antagonists for the ETA receptor have recently been isolated from Streptomyces fermentation products [6,7] and bayberry extracts [8] and prepared by chemical modification of ET-1 [9], but no antagonists selective to the ETa receptor have as yet been reported.…”

Section: Introductionmentioning

confidence: 99%

An endothelin B receptor‐selective antagonist: IRL 1038, [Cys¹¹‐Cys¹⁵]‐endothelin‐1(11–21)

et al. 1992

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In the inhibition of specific binding of [~:Sl]endothelins (ETs) to membranes from various tissues of rats, guinea pigs, pigs and humans, [Cys ~'-Cyst~]-ET-l( I 1-21 ), IRL 1038, has a much higher affinity for ETa receptors (Ki -6-11 nM) than for ET,., receptors (Ka = 0.4-0.7,a M). In contraction a.~ays, with ET-3 as a stimulant, 3 ,aM IRL 1038 antagonized the ET~ receptor-mediated contraction of guinea pig ileal and tracheal smooth muscle without any significant agonistie activity, but did not effect the ETA receptor-mediated contraction of rat aortic smooth muscle. IRL 1038 is, therefore, considered to be the first antagonist selective to the ETn receptor.

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Section: Introductionmentioning

confidence: 99%

An endothelin B receptor‐selective antagonist: IRL 1038, [Cys¹¹‐Cys¹⁵]‐endothelin‐1(11–21)

et al. 1992

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“…Peptide antagonists In order to develop new agonists and antagonists, as in the case of many bioactive peptides, modification of the endothelin and sarafotoxin amino acid sequences was attempted first and resulted in not only production of a series of agonists with varying potency, but also gave rise to a number of antagonists that were either selective or nonselective for the endothelin receptor subtypes. An important milestone in the development of useful tools for the study of endothelin was the isolation of a cyclic pentapeptide, BE-18257B, from the fermentation products of Streptomyces misakiensis (113). Further modification of BE-18257B has led to the identification of the cyclic pentapeptide BQ-123 (Banyu, Tokyo) with a higher affinity for the ETA receptor (114).…”

Section: -4 Intracellular Signal Transductionmentioning

confidence: 99%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

159

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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“…One approach to assessing whether the structure is a bioactive conformation is to compare it with an analogue molecule which is conformationally restricted and determine if there is any sensible overlap of crucial chemical moieties between the two. In 1991, a cyclic pentapeptide isolated from a fermentation broth of Streptomyces misakiensis was found to selectively inhibit the binding of ET-1 to the endothelin A receptor subtype and to functionally antagonize ET-1 induced vasoconstriction [18]. This molecule, cyclo(o-Trp-o-Glu-L-Ala-o-Alloile-L-Leu), has served as the lead structure from which a number of more potent analogues have been derived, most notably BQ123,…”

Section: Introductionmentioning

confidence: 99%

Comparison of the structures of the endothelin A receptor antagonists BQ123 andN‐methyl leucine BQ123 with the crystal structure of the C‐terminal tail of endothelin‐1

1995

FEBS Letters

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The functionally important regions of the cyclic pentapeptide endothelin A receptor antagonist BQ123 are shown to correlate with the structure of the C-terminal tail of endothelin-1, as found in the recently-determined X-ray crystal structure. Residues 18 and 21 of endothelin-1 are spatially juxtaposed such that they superpose extremely well with o-Asp and o-Trp of the antagonist, consistent with the residues on this surface of the endothelin helix being important for binding. This study provides new information on the three-dimensional nature of the endothelin A receptor binding site which may prove useful for rational drug design.

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An endothelin receptor (ETA) antagonist isolated from Streptomyces misakiensis

Cited by 188 publications

References 19 publications

An endothelin B receptor‐selective antagonist: IRL 1038, [Cys¹¹‐Cys¹⁵]‐endothelin‐1(11–21)

An endothelin B receptor‐selective antagonist: IRL 1038, [Cys¹¹‐Cys¹⁵]‐endothelin‐1(11–21)

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Comparison of the structures of the endothelin A receptor antagonists BQ123 andN‐methyl leucine BQ123 with the crystal structure of the C‐terminal tail of endothelin‐1

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An endothelin receptor (ETA) antagonist isolated from Streptomyces misakiensis

Cited by 188 publications

References 19 publications

An endothelin B receptor‐selective antagonist: IRL 1038, [Cys11‐Cys15]‐endothelin‐1(11–21)

An endothelin B receptor‐selective antagonist: IRL 1038, [Cys11‐Cys15]‐endothelin‐1(11–21)

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Comparison of the structures of the endothelin A receptor antagonists BQ123 andN‐methyl leucine BQ123 with the crystal structure of the C‐terminal tail of endothelin‐1

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An endothelin B receptor‐selective antagonist: IRL 1038, [Cys¹¹‐Cys¹⁵]‐endothelin‐1(11–21)

An endothelin B receptor‐selective antagonist: IRL 1038, [Cys¹¹‐Cys¹⁵]‐endothelin‐1(11–21)