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Identification of ligand-selective MR antagonists
Summary
We are working to identify differences in the activity of the MR in response to different ligands. This knowledge will form the basis for screening and the development of novel agents for the treatment of hypertension and cardiovascular disease.
Description
The aldosterone or mineralocorticoid receptor (MR) plays a central role in the pathophysiology of both cardiac failure and hypertension through direct effects on sodium balance and on the vascular system.
Drugs that block the MR are limited in clinical use due to unwanted side effects.
Although clinical trials have shown that MR blockers are very useful in the treatment of heart failure, the use of MR blockers for the treatment of heart failure is limited by side effects including hyperkalemia.
Drugs that block MR actions in the cardiovascular system, but not the kidney for example, would provide protection while limiting side effects.
We are working to identify differences in both tissue-selective and ligand-selective activity of the MR and to understand the molecular mechanisms of these differences.
This knowledge will form the basis for screening and development of novel agents for the treatment of hypertension and cardiovascular disease.
Funding
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National Health and Medical Research Council
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Williamson's Trust
Outcomes
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Reported interactions of the mineralcorticoid receptor that discriminate between aldosterone, cortisol and other naturally occuring steroid hormones.