The GnRH receptor is a member of the G protein-coupled receptor superfamily with seven predicted membrane spanning helices. Activation of the receptor stimulates phospholipase C and phosphatidyl inositol turnover by coupling to the GTP binding proteins Gq and G11.Peptide GnRH agonists can down-regulate pituitary gonadotrophic cells. Peptides also can suppress the hypothalamic-pituitary-gonadal axis. The GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases and reproductive disorders.

However, nonpeptide GnRH antagonists potentially offer several advantages over peptide GnRH analogs.

Today, we will introduce a novel, potent nonpeptide antagonist, NBI-42902. It suppresses serum LH concentrations in postmenopausal women after oral administration.

NBI-42902 is an orally active, potent functional and competitive antagonist of GnRH receptor for hormone-related diseases research

NBI-42902 is an orally active, potent functional and competitive antagonist of GnRH receptor with an IC50 value of 0.79 nM, a Ki value of 0.56 nM, respectively. Tritiated NBI-42902 binds with high affinity (Kd = 0.19 nM) to a single class of binding sites. It also can be displaced by a range of peptide and nonpeptide GnRH receptor ligands.

In vitro, NBI-42902 inhibits GnRH-stimulated inositol phosphate (IP) accumulation, Ca2+ flux, and ERK1/2 activation. Besides, NBI-42902 inhibits serum luteinizing hormone (LH) in castrated male macaques.

In vivo, NBI-42902 (0-1000 nM) is quite sensitive to the relatively conservative sequence changes between species, with IC50 values of 0.79 nM (human), 10 nM (macaque), 400 nM (dog), 200 nM (rabbit) for the GnRH receptors. Secondly, NBI-42902 (1 nM-1 μM, 1 min) inhibits GnRH (4 nM)-stimulated Ca2+ flux in RBL cells with a mean IC50 value of 3.6 nM. Meanwhile, NBI-42902 (1 nM-1 μM, 1 min) inhibits GnRH (4 nM)-induced IP accumulation competitively in RBL cells. And NBI-42902 (1 nM-1 μM, 5 min) blocks GnRH-stimulated ERK1/2 phosphorylation completely in CHO-GnRHR cells with an IC50 value of 5.22 nM. Furthermore, NBI-42902 (10-100 mg/kg, p.o. or i.v.) inhibits serum LH levels significantly in castrated macaques.

To sumup, NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor for research on sex-hormone-related diseases.


[1] Struthers RS, et al. 2007 Feb;148(2):857-67.