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Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist.
Abstract
Endothelins (ET) are potent vasoactive peptides implicated in the pathogenesis of a number of vascular diseases. The effects of ET on mammalian organs and cells are initiated by binding to ETA or ETB receptors. In this report, we document the pharmacology of A-127722, a novel ETA-selective receptor antagonist. A-127722 inhibits [125I]ET-1 binding to cloned human ETA and ETB receptors competitively with Ki values of 69 pM and 139 nM, respectively. A-127722 exhibits a dose-dependent inhibition of ET-1-induced arachidonic acid release in human pericardium smooth muscle cells with a pA2 value of 10.5 and inhibits ET-1-induced vasoconstriction in isolated rat aorta with a pA2 value of 9.2. In vivo, A-127722 dose-dependently blocks the pressor response to ET-1 (0.3 nmol/kg i.v.) in conscious rats. Statistically significant (P < .05) antagonism is seen at doses greater than 0.1 mg/kg p.o. Maximal inhibition, at 10 mg/kg, remains constant for at least 8 hr after dosing. No effect is seen on the ETB-mediated transient vasodepressor effect of exogenous ET-1. In conclusion, A-127722 is ETA-selective, orally bioavailable and efficacious for inhibiting the effects of ET in the rat, and A-127722 is the most potent ET receptor antagonist yet reported.
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Citations
Cited by
A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases
Yin, J. J., Mohammad, K. S., Käkönen, S. M., Harris, S., Wu-Wong, J. R., Wessale, J. L., Padley, R. J., Garrett, I. R., Chirgwin, J. M., & Guise, T. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1830978100 · Cited by 381
Self-citationCarducci, M. A., Padley, R. J., Breul, J., Vogelzang, N. J., Zonnenberg, B. A., Daliani, D. D., Schulman, C. C., Nabulsi, A. A., Humerickhouse, R. A., Weinberg, M. A., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.04.176 · Cited by 371
Kassab, S., Miller, M. T., Novak, J., Reckelhoff, J., Clower, B., & Granger, J. P. (1998) · Hypertension · doi:10.1161/01.hyp.31.1.397 · Cited by 110
Role of the endothelin axis and its antagonists in the treatment of cancer
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Metadata
- Authors
- Opgenorth, T. J., Adler, A. L., Calzadilla, S. V., Chiou, W. J., Dayton, B. D., Dixon, D. B., Gehrke, L. J., Hernandez, L., Magnuson, S. R., Marsh, K. C., Novosad, E. I., Von Geldern, T. W., Wessale, J. L., Winn, M., & Wu-Wong, J. R.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1996-02
- Volume
- 276
- Issue
- 2
- Pages
- 473-481
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1958247899
- Cited by
- 211
- References
- 0
- FWCI
- 8.47
- Type
- journal article
- Language
- en
- Open access
- closed
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- The paper
- Opgenorth, T. J., Adler, A. L., Calzadilla, S. V., Chiou, W. J., Dayton, B. D., Dixon, D. B., Gehrke, L. J., Hernandez, L., Magnuson, S. R., Marsh, K. C., Novosad, E. I., Von Geldern, T. W., Wessale, J. L., Winn, M., & Wu-Wong, J. R. (1996). Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist. The Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1016/s0022-3565(25)12297-0
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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