SB-334867-A: the first selective orexin-1 receptor antagonist

The pharmacology of various peptide and non-peptide ligands was studied in Chinese hamster ovary (CHO) cells stably expressing human orexin-1 (OX1) or orexin-2 (OX2) receptors by measuring intracellular calcium ([Ca2+](i)) us ing Fluo-3AM. Orexin-A and orexin-B increased [Ca2+](i) in CHO-OX1 (pEC(50) = 8.38 +/- 0.04 and 7.26 +/- 0.05 respectively, n = 12) and CHO-OX2 (pEC(5 0) = 8.20 +/- 0.03 and 8.26 +/- 0.04 respectively, n = 8) cells. However, n europeptide Y and secretin (10 pM-10 muM) displayed neither agonist nor ant agonist properties in either cell-line. SB-334867-A (1-(2-Methyylbenzoxanzo l-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride) inhibited the orexin-A (10 nM) and orexin-B (100 nM)-induced calcium responses (pK(B) = 7.27 +/- 0.04 and 7.23 +/- 0.03 respectively, n = 8), but had no effect on the UTP ( 3 muM)-induced calcium response in CHO-OX1 cells. SB-334867-A (10 muM) also inhibited OX2 mediated calcium responses (32.7 +/- 1.9% versus orexin-A). SB-334867-A was devoid of agonist properties in either cell-line. In conclu sion, SB-334867-A is a non-peptide OX1 selective receptor antagonist.