Abstract
Glucocorticoids have a pervasive role in human health and physiology. The endogenous members of this family are involved in a breadth of endocrine functions including metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance, as well as maintenance of immunological, renal and skeletal homeostasis. The predominant mode of action of glucocorticoids involves regulation of gene expression via the glucocorticoid receptor (GR). Synthetic glucocorticoids have long been the standard for the treatment of inflammatory and immune disorders, yet the benefits of classic steroids such as dexamethasone and prednisolone are accompanied by well-characterized potentiation of homeostatic endocrine functions, leading to the side effects associated with prolonged treatment. In recent campaigns for safer analogs, compounds have been sought which differentiate functional repression of existing transcription factors such as AP-1 and NFκB from GR-mediated transcriptional activation arising from binding at glucocorticoid-receptor response elements (GREs). Such differentiated ligands would provide the desired immunoregulatory actions without the endogenous changes in gene expression associated with undifferentiated steroids. We detail the methods for the evaluation of selective GR modulators and describe the evolution of new compounds where varying degrees of selectivity have been reported.
Keywords: glucocorticoid receptor, glucocorticoid-receptor response elements, gr-mediated transcriptional activation, homeostatic endocrine functions, prednisolone, classic steroids, dexamethasone
Current Topics in Medicinal Chemistry
Title: The Pursuit of Differentiated Ligands for the Glucocorticoid Receptor
Volume: 3 Issue: 14
Author(s): Michael J. Coghlan, Steven W. Elmore, Philip R. Kym and Michael E. Kort
Affiliation:
Keywords: glucocorticoid receptor, glucocorticoid-receptor response elements, gr-mediated transcriptional activation, homeostatic endocrine functions, prednisolone, classic steroids, dexamethasone
Abstract: Glucocorticoids have a pervasive role in human health and physiology. The endogenous members of this family are involved in a breadth of endocrine functions including metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance, as well as maintenance of immunological, renal and skeletal homeostasis. The predominant mode of action of glucocorticoids involves regulation of gene expression via the glucocorticoid receptor (GR). Synthetic glucocorticoids have long been the standard for the treatment of inflammatory and immune disorders, yet the benefits of classic steroids such as dexamethasone and prednisolone are accompanied by well-characterized potentiation of homeostatic endocrine functions, leading to the side effects associated with prolonged treatment. In recent campaigns for safer analogs, compounds have been sought which differentiate functional repression of existing transcription factors such as AP-1 and NFκB from GR-mediated transcriptional activation arising from binding at glucocorticoid-receptor response elements (GREs). Such differentiated ligands would provide the desired immunoregulatory actions without the endogenous changes in gene expression associated with undifferentiated steroids. We detail the methods for the evaluation of selective GR modulators and describe the evolution of new compounds where varying degrees of selectivity have been reported.
Export Options
About this article
Cite this article as:
Coghlan J. Michael, Elmore W. Steven, Kym R. Philip and Kort E. Michael, The Pursuit of Differentiated Ligands for the Glucocorticoid Receptor, Current Topics in Medicinal Chemistry 2003; 3 (14) . https://dx.doi.org/10.2174/1568026033451718
DOI https://dx.doi.org/10.2174/1568026033451718 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Anti-Ophidian Properties of Herbal Medicinal Plants: Could it be a Remedy for Snake Bite Envenomation?
Current Drug Discovery Technologies Exercise as Treatment for Neuropathy in the Setting of Diabetes and Prediabetic Metabolic Syndrome: A Review of Animal Models and Human Trials
Current Diabetes Reviews Nociceptin /Orphanin FQ Peptide (NOP) Receptor Modulators: An Update in Structure-Activity Relationships
Current Medicinal Chemistry Pharmacological Perspectives of Wasp Venom
Protein & Peptide Letters Endothelial Remodelling and Intracellular Calcium Machinery
Current Molecular Medicine Neutrophil Function in Severe Sepsis
Endocrine, Metabolic & Immune Disorders - Drug Targets Stable Gastric Pentadecapeptide BPC 157: Novel Therapy in Gastrointestinal Tract
Current Pharmaceutical Design Improvement of Nerve Fiber Density in Fibromyalgia Patients Treated with IVIg
Current Rheumatology Reviews Optimising the Use of Non-Invasive Ventilation in the Intensive Care Setting
Current Respiratory Medicine Reviews Beta-arrestin Biased Agonism/Antagonism at Cardiovascular Seven Transmembrane-spanning Receptors
Current Pharmaceutical Design Editorial (Thematic Issue: Antithrombotic Therapy: Current and Future Clinical Use)
Current Vascular Pharmacology Native Proteins in Organic Chemistry. Recent Achievements in the use of non Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Current Organic Chemistry Renal Endothelial Dysfunction in Acute Kidney Ischemia Reperfusion Injury
Cardiovascular & Hematological Disorders-Drug Targets Sida cordifolia, a Traditional Herb in Modern Perspective – A Review
Current Traditional Medicine Cardio-Vascular Risks Associated with Clozapine Treatment
Current Psychiatry Reviews A Practical Guide for the Treatment of Symptomatic Heart Failure with Reduced Ejection Fraction (HFrEF)
Current Cardiology Reviews Is Combined Angiotensin-converting Enzyme Inhibition and Angiotensin Receptor Blockade Associated with Increased Risk of Cardiovascular Death in Hemodialysis Patients?
Current Hypertension Reviews Disulfiram: An Old Therapeutic with New Applications
CNS & Neurological Disorders - Drug Targets Hypotensive Effects of the Triterpene Oleanolic Acid for Cardiovascular Prevention
Current Molecular Pharmacology Ischemic Neuronal Damage
Current Pharmaceutical Design