Reactome | NR3C2 binds NR3C2 antagonists

NR3C2 binds NR3C2 antagonists

Stable Identifier

R-HSA-9725855

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, extracellular region

ReviewStatus

5/5

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The mineralocorticoid receptor (Nuclear receptor subfamily 3 group C member 2, NR3C2) is a receptor with equal affinity for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. NR3C2 is expressed in many tissues such as kidney, heart, the CNS and sweat glands. Its activation leads to the expression of proteins regulating ionic and water transport resulting in the reabsorption of sodium. Consequently, there is an increase in extracellular volume, an increase in blood pressure, and increased excretion of potassium to maintain normal salt concentrations.

Synthetic NR3C2 antagonists competitively inhibit NR3C2 (Kagawa et al. 1957, Pollow et al. 1992, Rupprecht et al. 1993) in the kidney distal convoluted tubule to promote sodium and water excretion and potassium retention. These diuretic drugs are typically indicated for congestive heart failure, hypertension and chronic kidney disease. Synthetic antagonists of NR3C2 include the steroidal compounds spironolactone, eplerenone, and drospirenone. Nimodipine, a calcium channel blocker, can also act as an NR3C2 antagonist (Dietz et al. 2008, Luther 2014).

The broad clinical use of steroidal mineralocorticoid receptor antagonists is limited by the potential risk of inducing hyperkalemia. Novel, non-steroidal NR3C2 antagonists demonstrate an improved therapeutic index for hyperkalemic risk compared to their steroidal counterparts in preclinical models (reviews Kolkhof et al. 2015, Kolkhof & Bärfacker 2017, Sueta et al. 2020). Compounds undergoing clinical trials include apararenone (no trial data), esaxerenone (Arai et al. 2015), and finerenone (Bärfacker et al. 2012, Amazit et al. 2015).

Literature References

PubMed ID	Title	Journal	Year
13486053	Action of new steroids in blocking effects of aldosterone and desoxycorticosterone on salt KAGAWA, CM, CELLA, JA, VAN ARMAN, CG	Science	1957
8282004	Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands Rupprecht, R, Reul, JM, van Steensel, B, Spengler, D, Söder, M, Berning, B, Holsboer, F, Damm, K	Eur. J. Pharmacol.	1993
22791416	Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases Bärfacker, L, Kuhl, A, Hillisch, A, Grosser, R, Figueroa-Pérez, S, Heckroth, H, Nitsche, A, Ergüden, JK, Gielen-Haertwig, H, Schlemmer, KH, Mittendorf, J, Paulsen, H, Platzek, J, Kolkhof, P	ChemMedChem	2012
26073023	Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist Arai, K, Homma, T, Morikawa, Y, Ubukata, N, Tsuruoka, H, Aoki, K, Ishikawa, H, Mizuno, M, Sada, T	Eur J Pharmacol	2015
26203193	Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1 Amazit, L, Le Billan, F, Kolkhof, P, Lamribet, K, Viengchareun, S, Fay, MR, Khan, JA, Hillisch, A, Lombès, M, Rafestin-Oblin, ME, Fagart, J	J Biol Chem	2015
1493716	Dihydrospirorenone (ZK30595): a novel synthetic progestagen--characterization of binding to different receptor proteins Pollow, K, Juchem, M, Elger, W, Jacobi, N, Hoffmann, G, Möbus, V	Contraception	1992