Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: Survival of the fittest regulator of the immune system?

The search for novel glucocorticoid receptor (GR) modulators with similar anti-inflammatory properties as conventional steroids, but with a reduction in the number or severity of the side effects has been a long-standing goal, and still remains a challenge today. The quest for these so-called ‘dissociated GR ligands’ is mainly based on the hypothesis that the occurrence of undesirable side effects is mostly associated with GR-mediated transactivation, whereas transrepression of many pro-inflammatory genes (e.g. cytokines and enzymes involved in inflammatory processes) is more involved in GR-mediated anti-inflammatory effects. As glucocorticoids (GCs) can also enhance the transcription of anti-inflammatory genes, the GR-mediated activation – repression dissociation hypothesis has to be nuanced. However, an enhanced selectivity of GR-affected genes, while upholding the desired anti-inflammatory potential, is still believed to contribute to a more beneficial therapeutic profile with fewer side effects. The initial pharmacological focus on steroidal scaffolds as a basis to dissociate the functionalities of GR has, due to a lack of success, recently been shifted to a focus on non-steroidal ligands. The current work reviews recent advances on the characterization of a generation of novel non-steroidal GR ligands.

Research highlights
► Action mechanisms of the glucocorticoid receptor involved in immune regulation.
► Transactivation versus transrepression.
► The concept of dissociated GR modulators.
► Advances on novel nonsteroidal dissociated GR modulators.