A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.
Article Details
- CitationCopy to clipboard
Fagart J, Hillisch A, Huyet J, Barfacker L, Fay M, Pleiss U, Pook E, Schafer S, Rafestin-Oblin ME, Kolkhof P
A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.
J Biol Chem. 2010 Sep 24;285(39):29932-40. doi: 10.1074/jbc.M110.131342. Epub 2010 Jul 22.
- PubMed ID
- 20650892 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Spironolactone Glucocorticoid receptor Protein Humans UnknownAntagonistDetails Spironolactone Progesterone receptor Protein Humans UnknownAgonistDetails