SB-334867 hydrochloride is a potent, selective, and blood-brain barrier-permeable orexin-1 (OX1) receptor antagonist, with pKb of 7.4 for OX1 and pKi values of 5.4 and 5.3 for 5-HT2B and 5-HT2C, respectively[1]. SB-334867 hydrochloride reduces seizure activity by blocking hippocampal OX1 receptor activity, decreasing total glutamate content, and increasing total γ-aminobutyric acid content in the hippocampus[2]. SB-334867 hydrochloride has been widely used in animal models to inhibit the sympathetic nerve responses and temperature changes caused by stress[3].
In vitro, SB-334867 hydrochloride (1µM) treatment for 24 hours inhibited the expression of OX1R protein in BGC-823 cells stimulated by orexin A, reduced the level of phosphorylated AKT protein, and promoted cell apoptosis[4].
In vivo, a single intraperitoneal injection of SB-334867 hydrochloride at a dose of 30mg/kg 30 minutes before testing reduced ethanol intake and preference in high ethanol-preferring Sprague-Dawley rats[5]. Continuous intraperitoneal injection of SB-334867 hydrochloride (20mg/kg/day) for 28 consecutive days exacerbated cognitive dysfunction in the Alzheimer's disease mouse model and increased the expression levels of Aβ oligomers and p-tau in the hippocampus of the mice[6]. Continuous injection (i.c.v.) of 10µg/day dose of SB-334867 hydrochloride for 7 consecutive days inhibited the development of morphine analgesic tolerance in rats[7].
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[2] Socała K, Szuster-Ciesielska A, Wlaź P. SB 334867, a selective orexin receptor type 1 antagonist, elevates seizure threshold in mice[J]. Life sciences, 2016, 150: 81-88.
[3] Rusyniak D E, Zaretsky D V, Zaretskaia M V, et al. The orexin-1 receptor antagonist SB-334867 hydrochloride decreases sympathetic responses to a moderate dose of methamphetamine and stress[J]. Physiology & behavior, 2012, 107(5): 743-750.
[4] Wen J, Zhao Y, Shen Y, et al. Effect of orexin A on apoptosis in BGC-823 gastric cancer cells via OX1R through the AKT signaling pathway[J]. Molecular Medicine Reports, 2015, 11(5): 3439-3444.
[5] Moorman D E, Aston-Jones G. Orexin-1 receptor antagonism decreases ethanol consumption and preference selectively in high-ethanol–preferring Sprague–Dawley rats[J]. Alcohol, 2009, 43(5): 379-386.
[6] Gao W R, Hu X H, Yu K Y, et al. Selective orexin 1 receptor antagonist SB-334867 hydrochloride aggravated cognitive dysfunction in 3xTg-AD mice[J]. Behavioural Brain Research, 2023, 438: 114171.
[7] Ranjbar-Slamloo Y, Azizi H, Fathollahi Y, et al. Orexin receptor type-1 antagonist SB-334867 hydrochloride inhibits the development of morphine analgesic tolerance in rats[J]. Peptides, 2012, 35(1): 56-59.