Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist.

High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.

Effect of the glucocorticoid receptor antagonist Org 34850 on fast and delayed feedback of corticosterone release.

We investigated the effect of the glucocorticoid receptor (GR) antagonist Org 34850 on fast and delayed inhibition of corticosterone secretion in response to the synthetic glucocorticoid methylprednisolone (MPL). Male rats were implanted with a catheter in the right jugular vein, for blood sampling and MPL administration, and with an s.c.

Acute oral dexamethasone administration reduces levels of orphan GPCR glucocorticoid-induced receptor (GIR) mRNA in rodent brain: potential role in HPA-axis function.

Glucocorticoid-induced receptor (GIR) is an orphan G-protein-coupled receptor (GPCR) with predominant expression in brain and thymus. More specifically, high levels of GIR expression have been described in brain regions of mouse, rat and human including limbic forebrain and hypothalamic regions, suggesting a role for GIR in memory, cognition, stress, reward or the control of emotion. Previous in vitro studies performed in murine thymocytes demonstrated an induction of GIR following dexamethasone treatment, suggesting the potential in vivo regulation of GIR by glucocorticoids.