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 G_q 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 K_i value of 0.56 nM, respectively. Tritiated NBI-42902 binds with high affinity (K_d = 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.

Reference:

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