Received October 24, 2006
Revised November 10, 2006
Accepted after revision November 21, 2006
Neuroendocrinology/Endocrinology [270]
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Modelling the glucocorticoid receptor and producing
therapeutic agents with anti-inflammatory effects but
reduced side-effects
andrew mcmaster 1
David Ray 1*
1 University of Manchester
* To whom correspondence should be addressed. E-mail: david.w.ray{at}man.ac.uk.
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Abstract |
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Summary
Glucocorticoid hormones exert a wide spectrum of metabolic, and immunological effects. They are synthesised from a cholesterol precursor, and are structurally related to the other steroid hormones, progesterone, aldosterone, and oestrogen. They act through the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. The GR is an intracellular receptor; the hydrophobic ligand accesses its receptor by diffusion across the plasma membrane. The ligand activated GR translocates to the nucleus to regulate expression of its target genes. The GR, in common with the rest of the receptor family, can be functionally divided into an N terminal transcription activation domain, a central DNA biding domain, and a C terminal ligand binding domain, which also includes a second transactivation domain. Although synthetic glucocorticoids are the most potent anti-inflammatory agents known their use is limited due to the range and severity of their side-effects. The structure of the ligand binding domain of the glucocorticoid receptor has now been solved, and a series of studies has shown that even subtle changes to the ligand structure alter the final conformation of the ligand-receptor complex, with consequences for further protein recruitment, and function of the receptor. This, coupled with the successful development of selective oestrogen receptor agonists, has led to concerted efforts to find selective GR ligands, with preserved, beneficial, anti-inflammatory activity, but reduced side-effect profile. Current efforts have identified several useful tool compounds, and further molecules are in development in several pharmaceutical companies
Key Words:
Adrenal gland, Adrenal medulla, Adrenaline
