SB-334867 (SB 334867A) is a potent, selective, and blood-brain barrier permeable antagonist of the orexin-1 (OX1) receptor, demonstrating significant selectivity against OX2 (pKb=7.4), and exhibiting 100-fold selectivity over 5-HT2B and 5-HT2C, with pKi values of 5.4 and 5.3, respectively [1]. This compound effectively reduces ethanol consumption and obstructs the development of morphine-induced sensitization to locomotor activity in vivo [2] [3].

SB-334867, ranging from 100 pM to 10 μM, selectively blocks calcium responses induced by orexin-A (10 nM) and orexin-B (100 nM) in a concentration-dependent fashion, exhibiting pKb values of 7.27±0.04 and 7.23±0.03, respectively. It does not impact the calcium response triggered by UTP (3 μM), which stimulates a native purinergic receptor in CHO-OX1 and CHO-OX2 cells [4].

SB-334867, administered via intraperitoneal injection at dosages of 20 mg/kg for 20 days and 15 minutes before morphine, significantly diminishes the impact of a morphine challenge dose in mice compared to a control group receiving sporadic morphine treatments. Similarly, doses of 3, 10, and 30 mg/kg of SB-334867 markedly decrease ethanol consumption in female P rats without affecting water intake, with the 30 mg/kg dosage notably reducing ethanol consumption, suppressing sucrose intake when compared to vehicle treatment, and resulting in lower blood ethanol concentrations (BECs) than both the 10 and 30 mg/kg dosages. In male Swiss mice, a 20 mg/kg dose inhibits the development of morphine-induced sensitization to locomotor activity. In C57BL/6J mice, the same compound at dosages of 3, 10, and 30 mg/kg reduces ethanol intake, BECs, and suppresses sucrose consumption.