title: Towards selectively modulating mineralocorticoid receptor function: lessons from other systems.
abstract: Although there is clinical utility in blocking mineralocorticoid receptor (MR) action, the usefulness of available MR antagonists is limited because of cross-reactivity with the androgen and progesterone receptors (spironolactone) or possibly by low affinity for MR (eplerenone). MR binds aldosterone and physiologic glucocorticoids, such as cortisol, which both can act as MR agonists in epithelial tissues. However, in preliminary studies aldosterone and cortisol appear to induce different conformations in non-epithelial tissues; in the cardiomyocyte, cortisol usually acts as an MR antagonist, whereas in vascular smooth muscle cortisol mimics aldosterone actions if it can access MR, just as it does in the kidney. Thus, there are needs for improved MR antagonists with higher selectivity and potency and, if possible, for compounds that lock MR into specific desirable conformations. Efforts are underway to modulate selectively the action of many nuclear receptors, and insights from one nuclear receptor may be applicable to others given the similarities in structure and function. We have used traditional approaches aided by X-ray crystallography to obtain several classes of selective ligands that modulate thyroid receptor (TR) action. We describe the properties of these selective TR modulators here, and discuss the possibility that similar approaches to ligand design may yield MR interacting compounds with improved specificity and, possibly, tissue specificity.
authors.affiliation: Diabetes Center and Metabolic Research Unit, University of California-San Francisco, San Francisco, CA 94143-0540, USA. jbaxter918@aol.com
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: James W
authors.initials: JW
authors.lastname: Apriletti
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004848:Epithelium / Q000502:physiology; D000077545:Eplerenone; D006854:Hydrocortisone / Q000008:administration & dosage / Q000378:metabolism*; D000451:Mineralocorticoid Receptor Antagonists / Q000737:chemistry; D032383:Myocytes, Cardiac / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011988:Receptors, Thyroid Hormone; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D006854:Hydrocortisone