S-0139 (27-O-3-[2-(3-carboxy-acryloylamino)-5-hydroxyphenyl]-acryloylo xy myricerone, sodium salt) is a highly specific nonpeptide endothelin ET(A) receptor antagonist. The binding of [3H]S-0139 was compared to that of [125I]endothelin-1 to characterize the binding of the antagonist in porcine aortic smooth muscle membranes. Scatchard analysis revealed a single class of [3H]S-0139 binding sites with a Kd value of 0.61 +/- 0.10 nM and a Bmax of 0.72 +/- 0.16 pmol/mg protein. These sites were saturable and reversible. [125I]Endothelin-1 also showed binding with high affinity (Kd = 0.12 +/- 0.02 nM) to a homogeneous population of binding sites, whose Bmax (0.71 +/- 0.20 pmol/mg protein) was almost the same as that for [3H]S-0139. In both cases, the binding could be displaced by known endothelin receptor ligands and their IC50 values in each case showed a very close correlation (r = 0.986). The potency of seven endothelin receptor antagonists to displace [3H]S-0139 binding also correlated highly to the potency for inhibiting the endothelin-1-induced increase in cytosolic Ca2+ concentration (r = 0.949). Myriceric acid A showed a more potent functional activity than expected from its binding affinity, but this seemed to result from the different assay conditions, such as incubation time. Together, the results suggest that S-0139 labels only endothelin ET(A) receptor binding sites in porcine aortic smooth muscle.

1996-02-01·British Journal of Pharmacology

Characterization of the endothelin receptor selective agonist, BQ3020 and antagonists BQ123, FR139317, BQ788, 50235, Ro462005 and bosentan in the heart

Article

作者: Anthony P. Davenport ; Markus G. Peter

In this study we used ligand binding techniques to determine the affinity and selectivity of endothelin receptor agonists and antagonists in human left ventricle which expresses both ETA and ETB receptors, and compared these results with cardiovascular tissues from rat and porcine hearts.

The linear tripeptide antagonist, FR139317 competed for [125I]‐ET‐1 binding to human left ventricle with over 200,000 fold selectivity for the ETA receptor (KD ETA=1.20±0.28 nM, KDETB = 287±93 μm). The ETA‐selective non‐peptide antagonist, 50235, competed with lower affinity and selectivity (KDETA = 162±61 nM, KDETB= 171±42 μm) in this tissue. BQ123 and FR139317 also showed high selectivity (greater than 20,000 fold) and affinity in rat (BQ123: KDETA = 1.18±0.16 nM, KDETB = 1370±1150 μm; FR139317: KDETA = 2.28±0.30 nM, KDETB = 292±114 μm) and pig heart (BQ123: KDETA = 0.52±0.05 nM, KDETB = 70.4±4.0 μm; FR139317: KDETA = 2.17±0.51 nM, KDETB = 47.1±5.7 μm) (n≥3 individuals±s.e.mean).

Although BQ3020 competed with over 1000 fold selectivity for the ETB subtype in human heart KDETB = 1.38±0.72 nM, KDETA = 2.04±0.21 μm) the peptide inhibited only the binding of [125I]‐ET‐1 at concentrations greater than 100 nM in rat and porcine heart. This is in contrast to the data from the ETA‐selective antagonists which indicated the presence of ETB sites in these tissues from animal hearts.

The peptide antagonist, BQ788, had a low, micromolar affinity (KD = 1.98±0.13 μm) using human left ventricle and no significant selectivity for the human ETB‐subtype in this tissue.

The non‐peptide ET antagonists, Ro462005 (KD = 50.3±9.5 μm) and bosentan (Ro470203; KD = 77.9±7.9 nM) competed monophasically for [125I]‐ET‐1 binding sites in human left ventricle.

The results show that the ETA antagonists, BQ123 and FR139317, are highly selective for ETA receptors in all cardiac tissues tested, whereas BQ788 has a low affinity and no selectivity in this human tissue. Further we showed that there are species differences in the binding of BQ3020 to the ETB receptors in the hearts derived from human, rat and pig.

1996-01-01·Chemical and Pharmaceutical Bulletin4区 · 医学

Endothelin Receptor Antagonist Triterpenoid, Myriceric Acid A, Isolated from Myrica cerifera, and Structure Activity Relationships of Its Derivatives.

4区 · 医学

Article

作者: Kikuchi, Junko ; Sakurawi, Kensuke ; Terui, Yoshihiro ; Sato, Tomohiro ; Tozyo, Takehiko ; Nakamura, Miharu ; Yasuda, Fumio ; Ikenishi, Yuji ; Itata, Tsuyoshi

As the first non-peptide endothelin receptor antagonist from a higher plant, a new triterpenoid, myriceric acid A (50-235) (1) was isolated from the bayberry, Myrica cerifera. Myriceric acid A (1) inhibited not only an endothelin-1-induced increase in cytosolic free Ca2+ concentration (IC50 = 11 +/- 2 nM) but [125I]endothelin-1 binding in rat aortic smooth muscle cells (Ki = 66 +/- 15 nM). Two new related triterpenoids, myriceric acid C (6), and myriceric acid D (8), were also isolated. Furthermore, the chemical modification of these natural products led to the synthesis of sulfated derivatives (13, 14, 15) which showed 1.5 to 20 times higher affinity for endothelin receptors. The structure activity relationships of myriceric acids and their derivatives are discussed.

100 项与 50-235 相关的药物交易

登录后查看更多信息