A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.

The Journal of Biological Chemistry
J FagartPeter Kolkhof

Abstract

Limitations of current steroidal mineralocorticoid receptor (MR) antagonists have stimulated the search for a new generation of molecules. We screened for novel nonsteroidal compounds and identified MR antagonists derived from the chemical class of dihydropyridines. Chemical optimization resulted in BR-4628, which displays high in vitro and in vivo MR potency as well as selectivity with respect to the other steroid hormone receptors and the L-type calcium channel. Biochemical studies demonstrated that BR-4628 forms complexes with MR that do not promote the recruitment of transcriptional co-regulators. Docking experiments, using the crystal structure of the MR ligand-binding domain in an agonist conformation, revealed that BR-4628 accommodates in the MR ligand-binding cavity differently in comparison with the classical steroidal MR antagonists. An alanine scanning mutagenesis approach, based on BR-4628 docking, allowed identifying its anchoring mode within the ligand-binding cavity. Altogether, we propose that BR-4628 is a bulky antagonist that inactivates MR through a passive mechanism. It represents the prototype of a new class of MR antagonists.

References

Mar 1, 1992·Hypertension·J D Horisberger, B C Rossier
Jan 1, 1989·Journal of Steroid Biochemistry·M de GasparoJ Ménard
Oct 1, 1987·The American Journal of Cardiology·X JeunemaitreJ Menard
Jun 17, 1998·Molecular Endocrinology·B CouetteM E Rafestin-Oblin
Jun 17, 1998·The EMBO Journal·J FagartM E Rafestin-Oblin
Sep 15, 1998·Kidney International. Supplement·R C HarrisJ A McKanna
Oct 28, 1999·Cardiovascular Research·C Delcayre, J S Silvestre
Aug 6, 2002·American Journal of Hypertension·Myron H WeinbergerRobert J Weiss
Apr 2, 2003·The New England Journal of Medicine·Bertram PittUNKNOWN Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators
May 12, 2004·Molecular and Cellular Endocrinology·Susan M Garthwaite, Ellen G McMahon
Mar 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·G J Kleywegt, T A Jones
Jan 6, 2005·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·Katherine F Croom, Caroline M Perry
Feb 18, 2005·Molecular Pharmacology·Jérôme FagartMarie-Edith Rafestin-Oblin
Apr 19, 2005·Proceedings of the National Academy of Sciences of the United States of America·Casey E BohlJames T Dalton
Apr 30, 2005·The Journal of Steroid Biochemistry and Molecular Biology·John W Funder
May 24, 2005·Nature Structural & Molecular Biology·Jérôme FagartMarie-Edith Rafestin-Oblin
Jun 22, 2005·The Journal of Biological Chemistry·Randy K BledsoeShawn P Williams
Sep 1, 2005·The Journal of Biological Chemistry·Casey E BohlJames T Dalton
Apr 14, 2006·Journal of the American Society of Nephrology : JASN·David S GellerRichard P Lifton
Aug 25, 2006·Nature Clinical Practice. Endocrinology & Metabolism·John W Funder
Jun 16, 2007·Molecular Pharmacology·Jessica HuyetMarie-Edith Rafestin-Oblin
Feb 29, 2008·Journal of Pharmacological and Toxicological Methods·Philip E BrandishJames C Hershey
May 27, 2008·The Journal of Steroid Biochemistry and Molecular Biology·Junhui Zhang, David S Geller
Nov 1, 2008·Journal of the American Society of Hypertension : JASH·David A Calhoun, William B White

❮ Previous
Next ❯

Citations

May 31, 2013·Current Atherosclerosis Reports·Adam P McGrawIris Z Jaffe
Mar 21, 2012·Nature Reviews. Cardiology·Ludovit PaulisThomas Unger
Oct 17, 2012·Nature Reviews. Nephrology·Sara S RoscioniHiddo J Lambers Heerspink
Oct 10, 2012·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Michel AziziJoël Menard
Sep 27, 2012·Journal of Hypertension·GianLuca ColussiLeonardo A Sechi
Dec 14, 2011·The Journal of Endocrinology·Peter J FullerMorag J Young
May 8, 2014·International Journal of Inflammation·Maricica PacurariKenneth Ndebele
Jan 31, 2013·Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology·Lea R Medeiros, M Danielle McDonald
Jul 6, 2014·Current Opinion in Nephrology and Hypertension·James M Luther
Jul 14, 2014·Seminars in Nephrology·Juan TamargoLuis M Ruilope
May 6, 2014·Current Hypertension Reports·Michael Stowasser
Sep 13, 2015·Journal of the American Society of Nephrology : JASN·Jonatan Barrera-ChimalFrédéric Jaisser
Sep 13, 2015·Journal of the American Society of Nephrology : JASN·Luis A Juncos, Luis I Juncos
Dec 5, 2015·European Journal of Heart Failure·Peter BramlageRoland E Schmieder
Dec 21, 2012·Kidney International·Joseph F GnanarajJai Radhakrishnan
Mar 13, 2014·The Journal of Sexual Medicine·Katrien WierckxGuy T'sjoen
Apr 6, 2012·Pharmacology & Therapeutics·Doron Aronson, Henry Krum
Aug 9, 2011·Molecular and Cellular Endocrinology·Jessica HuyetJérôme Fagart
Jul 26, 2011·Molecular and Cellular Endocrinology·Jun Yang, Peter J Fuller
Jul 21, 2011·Molecular and Cellular Endocrinology·Peter Kolkhof, Steffen A Borden
Mar 5, 2016·Current Opinion in Pharmacology·Jun Yang, Morag J Young
Feb 11, 2015·The Journal of Investigative Dermatology·Eve MaubecNicolette Farman
Jan 28, 2014·European Journal of Heart Failure·Javaid IqbalFaiez Zannad
Apr 15, 2016·International Journal of Cardiology·Vincenzo MollaceFrancesco Rossi
Sep 11, 2014·The Journal of Steroid Biochemistry and Molecular Biology·I Petit-TopinJ Fagart
Jul 28, 2015·Pharmacology & Therapeutics·Jaap DeinumJacques W M Lenders
Jan 25, 2014·Expert Opinion on Pharmacotherapy·Juan TamargoLuis M Ruilope
Nov 13, 2013·Expert Opinion on Therapeutic Patents·Matthieu CollinFrédéric Jaisser
Jan 18, 2013·Expert Opinion on Therapeutic Targets·Morag J Young
Feb 25, 2015·Trends in Endocrinology and Metabolism : TEM·Yasir ParvizFaiez Zannad
Feb 11, 2015·Molecular and Cellular Endocrinology·Peter J Fuller
Apr 25, 2015·Advances in Chronic Kidney Disease·John M Hamlyn, Paolo Manunta
Feb 11, 2015·Nature Reviews. Endocrinology·Cesar A RomeroMatthew R Weir
Sep 25, 2014·Annual Review of Pharmacology and Toxicology·Achim LotherLutz Hein
Aug 11, 2016·Metabolism: Clinical and Experimental·Pingping YangGaosi Xu
Jul 28, 2016·Pharmacology & Therapeutics·Achim Lother, Lutz Hein

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.