Selective Glucocorticoid Receptor Agonist - Mechanism of Action

Mechanism of Action

Both non-selective glucocorticoids and selective glucocorticoid receptor agonists work by binding to and activating the glucocorticoid receptor (GR). In contrast to glucocorticoids, which activate the GR to work through two signal transduction pathways, SEGRAs activate the GR in such a way that it only operates through one of the two possible pathways.

In the absence of glucocorticoids, the GR resides in the cytosol in an inactive state complexed with heat shock proteins (HSPs). Binding of glucocorticoids to the GR activates the receptor by causing dissociation of the bound HSPs. The activated GR can then regulate gene expression via one of two pathways:

• The first (direct) pathway is called transactivation whereby the activated GR dimerizes, is translocated into the nucleus and binds to specific sequences of DNA called glucocorticoid response elements. The GR/DNA complex recruits other proteins which transcribe downstream DNA into mRNA and eventually protein. Examples of glucocorticoid responsive genes include those that encode annexin A1, angiotensin-converting enzyme, neutral endopeptidase and other anti-inflammatory proteins.

• The second (indirect) pathway is called transrepression, in which activated monomeric GR binds to other transcription factors such as NF-κB and AP-1 and prevents these from up-regulating the expression of their target genes. These target genes encode proteins such as cyclooxygenase, NO synthase, phospholipase A2, tumor necrosis factor, transforming growth factor beta, ICAM-1, and a number of other pro-inflammatory proteins.

Hence the anti-inflammatory effects of glucocorticoids results from both transactivation and transrepression. In contrast, studies in rats have shown that most of the side-effects of glucocorticoids, such as diabetogenic activity, osteoporosis, as well as skin atrophy, are caused by transactivation. A selective glucocorticoid that is able to transrepress without transactivation should preserve many of the desirable therapeutic anti-inflammatory effects and minimize undesired side effects.

Strong evidence that transpression alone is sufficient for an anti-inflammatory response was provided by introducing a point mutation in the GR of mice that prevented GR from dimerizing and binding to DNA and thereby blocking transactivation. At same time, this mutation did not interfere with transrepression. While GR is essential for survival, these mice are still viable. However, when these mice were treated with the synthetic glucocorticoid dexamethasone, there was no elevation of glucose. At the same time, these dexamethsone treated mice were resistant to inflammatory stimulus. Hence these mice were responsive to the anti-inflammatory effects of dexamethasone but were resistant to at least some of the side-effects.

Just like glucocorticoids, SEGRAs bind to and activate GR. However in contrast to glucocorticoids, SEGRAs selectively activate the GR such that they more strongly transrepress than transactivate. This should result in fewer side effecs.