SB-334867-A is the first selective and non-peptide orexin-1 receptor antagonist with pKB values of 7.27 and 7.23 for inhibition of the orexin-A (10 nM) and orexin-B (100 nM)-induced calcium responses, respectively, but had no effect on the UTP (3μM)-induced calcium response in CHO-OX1 cells. SB-334867-A inhibited OX2 mediated calcium responses up to 10μM. A single intraperitoneal injection with SB-334867-A at dose of 30mg/kg during the light phase reduced both orexin-A-induced food intake and feeding stimulated by an overnight fast for 4h in male rats. Daily injections with SB-334867-A at the start of the dark phase for 3 days reduced natural feeding in male rats over 24 h on day 1 and day 3. SB-334867-A possesses blood–brain barrier permeability shown as CNS penetration ratio brain/blood ratio of 0.4:1.
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