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Drug Insight: selective agonists and antagonists of the glucocorticoid receptor

Nature Clinical Practice Endocrinology & Metabolism volume 4, pages 91–101 (2008)Cite this article

Abstract

Glucocorticoid hormones exert a wide spectrum of metabolic and immunological effects. They function through the glucocorticoid receptor, a member of the nuclear receptor superfamily. Glucocorticoids are particularly effective as anti-inflammatory agents but often cause severe side effects. The structure of the ligand-binding domain of the glucocorticoid receptor has now been elucidated, and a series of studies have shown that even subtle changes to the ligand structure alter the final conformation of the ligand–receptor complex, with consequences for both protein recruitment and the function of the receptor. This has led to concerted efforts to find selective ligands for the glucocorticoid receptor that preserve the beneficial anti-inflammatory activity but reduce the side-effect profile. The direct health-care benefits of such a simple, safe, orally active agent targeting the underlying inflammatory process in, for example, rheumatoid arthritis would be considerable in terms of reduced patient suffering; furthermore, the indirect benefits in terms of reducing the costs of therapeutic delivery and preventing loss of productivity would be even greater.

Key Points

  • Glucocorticoids are the most potent anti-inflammatory agents known

  • Their use is limited by a wide spectrum of severe side effects

  • The mechanisms of action of glucocorticoids differ between anti-inflammatory and metabolic effects

  • Structural studies of the glucocorticoid receptor have enabled rational drug design

  • Novel ligands hold the promise of selective anti-inflammatory activity

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Figure 1: Structures of three natural ligands that bind the glucocorticoid receptor and four drugs that also bind it.
Figure 2: Mechanisms of glucocorticoid receptor action.
Figure 3: Structure of the glucocorticoid receptor.
Figure 4: Model of ligand interpretation by the glucocorticoid receptor and selective comodulator recruitment.

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Acknowledgements

The authors receive funding from the Arthritis Research Campaign, the Medical Research Council, the Wellcome Trust, and GlaxoSmithKline. We thank Tracy Bent and Anthony McGowan for help in preparing the manuscript.

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  1. A McMaster is a PhD student, and DW Ray is Professor of Medicine and Endocrinology, at the Centre for Molecular Medicine, School of Clinical and Laboratory Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.,

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Correspondence to David W Ray.

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A McMaster declared no competing interests. DW Ray has received research funding from GlaxoSmithKline, as a GlaxoSmithKline Clinical Research Fellow, and holds patents relating to novel ligands for the glucocorticoid receptor.

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McMaster, A., Ray, D. Drug Insight: selective agonists and antagonists of the glucocorticoid receptor. Nat Rev Endocrinol 4, 91–101 (2008). https://doi.org/10.1038/ncpendmet0745

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