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 (OX 1 ) or orexin‐2 (OX 2 ) receptors by measuring intracellular calcium ([Ca 2+ ] i ) using Fluo‐3AM. Orexin‐A and orexin‐B increased [Ca 2+ ] i in CHO‐OX 1 (pEC 50 =8.38±0.04 and 7.26±0.05 respectively, n =12) and CHO‐OX 2 (pEC 50 =8.20±0.03 and 8.26±0.04 respectively, n =8) cells. However, neuropeptide Y and secretin (10 p M  – 10 μ M ) displayed neither agonist nor antagonist properties in either cell‐line. SB‐334867‐A (1‐(2‐Methyylbenzoxanzol‐6‐yl)‐3‐[1,5]naphthyridin‐4‐yl‐urea hydrochloride) inhibited the orexin‐A (10 n M ) and orexin‐B (100 n M )‐induced calcium responses (p K B =7.27±0.04 and 7.23±0.03 respectively, n =8), but had no effect on the UTP (3 μ M )‐induced calcium response in CHO‐OX 1 cells. SB‐334867‐A (10 μ M ) also inhibited OX 2 mediated calcium responses (32.7±1.9% versus orexin‐A). SB‐334867‐A was devoid of agonist properties in either cell‐line. In conclusion, SB‐334867‐A is a non‐peptide OX 1 selective receptor antagonist. British Journal of Pharmacology (2001) 132 , 1179–1182; doi: 10.1038/sj.bjp.0703953