Cited by 122Stress Responses and CortisolEstrogen and related hormone effectsAdrenal Hormones and Disorders

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Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

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Zalachoras, Ioannis, Houtman, René, Atucha, Erika, Devos, Rene, Tijssen, Ans M. I., Hu, Pu, Lockey, Peter M., Datson, Nicole A., Belanoff, Joseph K., Lucassen, Paul J., Joëls, Marian, de Kloet, E. Ronald, Roozendaal, Benno, Hunt, Hazel, Meijer, Onno C.·2013·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1219411110PMC PMC3651427

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Abstract

Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels. Selective GR modulators are ligands that can act both as agonist and as antagonist and may be used to separate beneficial from harmful treatment effects. We have discovered that the high-affinity GR ligand C108297 is a selective modulator in the rat brain. We first demonstrate that C108297 induces a unique interaction profile between GR and its downstream effector molecules, the nuclear receptor coregulators, compared with the full agonist dexamethasone and the antagonist RU486 (mifepristone). C108297 displays partial agonistic activity for the suppression of hypothalamic corticotropin-releasing hormone (CRH) gene expression and potently enhances GR-dependent memory consolidation of training on an inhibitory avoidance task. In contrast, it lacks agonistic effects on the expression of CRH in the central amygdala and antagonizes GR-mediated reduction in hippocampal neurogenesis after chronic corticosterone exposure. Importantly, the compound does not lead to disinhibition of the hypothalamus–pituitary–adrenal axis. Thus, C108297 represents a class of ligands that has the potential to more selectively abrogate pathogenic GR-dependent processes in the brain, while retaining beneficial aspects of GR signaling.

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Authors: Zalachoras, I., Houtman, R., Atucha, E., Devos, R., Tijssen, A. M. I., Hu, P., Lockey, P. M., Datson, N. A., Belanoff, J. K., Lucassen, P. J., Joëls, M., de Kloet, E. R., Roozendaal, B., Hunt, H., & Meijer, O. C.
Affiliations: Leiden University Medical Center (NL)
PamGene (Netherlands) (NL)
Radboud University Nijmegen (NL)
Argenta Discovery, Harlow, Essex CM19 5TR, United Kingdom;
Division Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, 2300 RA Leiden, The Netherlands;
University of Amsterdam (NL)
Corcept Therapeutics (United States) (US)
University Medical Center Utrecht (NL)
ORCID: Zalachoras, Ioannis
Houtman, René
Atucha, Erika
Datson, Nicole A.
Lucassen, Paul J.
Joëls, Marian
Roozendaal, Benno
Hunt, Hazel
Meijer, Onno C.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2013-04-23
Volume: 110
Issue: 19
Pages: 7910-7915
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1219411110
PMC: PMC3651427
OpenAlex: W2161618887
Cited by: 121
References: 50
Citations by year: 2026: 4 · 2025: 1 · 2024: 6 · 2023: 11 · 2022: 9 · 2021: 6 · 2020: 4 · 2019: 15 · 2018: 15 · 2017: 10 · 2016: 16 · 2015: 8 · 2014: 9 · 2013: 7
FWCI: 6.05
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
UvA-DARE (University of Amsterdam) (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Leiden Repository (Leiden University) (submittedVersion)
UvA-DARE (University of Amsterdam) (submittedVersion)
Radboud Repository (Radboud University) (submittedVersion)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords: glucocorticoid receptor, selective glucocorticoid receptor modulators, depression, corticotropin-releasing factor, hypothalamus, central amygdala, hippocampal neurogenesis, hypothalamic-pituitary-adrenal axis, nuclear receptor coregulators, dexamethasone, mifepristone, chronic corticosterone
MeSH terms: Animals, Brain, Corticotropin-Releasing Hormone, Dexamethasone, Gene Expression Regulation, Hippocampus, Ligands, Male, Peptides, Receptors, Glucocorticoid, Steroids, Time Factors, Transcription, Genetic, Mifepristone, Rats, Sprague-Dawley, Two-Hybrid System Techniques, Rats, Nuclear Receptor Coactivator 1

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Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

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