SB-408124 is a non-peptide antagonist for OX1 receptor with Ki of 57 nM and 27 nM in both whole cell and membrane, respectively, and exhibits 50-fold selectivity over OX2 receptor.
Orexins (A and B) are hypothalamic peptides that interact with OX1 and OX2 receptors and are involved in the sleep/wake cycle. OX1 receptors are highly expressed in colon cancer tumours and colonic cancer cell lines where orexins induce apoptosis and inhibit tumour growth in preclinical animal models[3]. Injection of exogenous orexin-A specifically improved the inflammatory symptoms in the two colitis murine models. Conversely, injection of inactive orexin-A analog, OxB7-28 or OX1R specific antagonist SB-408124 did not have anti-inflammatory effect. Moreover, treatment with orexin-A in DSS-colitis induced OX1R-/- knockout mice did not have any protective effect. The orexin-A anti-inflammatory effect was due to the decreased expression of pro-inflammatory cytokines in immune cells and specifically in T-cells isolated from colonic mucosa[4].SB-408124 is a non-peptide OX1 receptor antagonist with Kis of 57 nM and 27 nM in whole cell and membrane, respectively. SB-408124 exhibits 50-fold selectivity over OX2 receptor[5]. SB-408124 (30 μg/10 μl; i.c.v.; male Wistar rats) decreases Orexin-A induced water intake in Wistar rats[6].In isolated rat cardiomyocytes, only orexin-B (OR-B) caused an increase in contractile shortening, independent of diastolic or systolic calcium levels. A specific orexin receptor-2 (OX2R) agonist ([Ala11, d-Leu15]-Orexin B) exerted similar effects as OR-B, whereas a specific orexin receptor-1 (OX1R) antagonist (SB-408124) did not alter the responsiveness of OR-B[7].
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