SB-649868 is a potent and selective orally active orexin (OX) 1 and OX2 receptor antagonist (pKi =9.4 and 9.5 at the OX1 and OX2 receptor, respectively).
The orexin-1 (OX1) and orexin-2 (OX2) receptors are G-protein coupled receptors profoundly implicated in sleep disorders. SB-649868 is a dual OX1 and OX2 receptor antagonist with pKi values of 9.4 and 9.5 for
human OX1 and OX2 receptors, respectively. It demonstrates higher functional potencies for rat OX1 and OX2 receptors with pKi values of 9.93 and 10.11, respectively. The in vitro clearance of SB-649868 in rat and human liver microsomes was 8.7 and 15.1mL/min/g, respectively. SB-649868 displaced [3H]almorexant in Chinese hamster ovary cells overexpressing both human recombinant OX1 and OX2 receptors in a concentration dependent manner, with pKi values of 9.12 and 8.89, respectively, In rats subjected to intracerebroventricular injection of neuropeptides orexin-A (OX-A), oral administration of SB-649868 (3 and 10mg/kg) 3 hours before OX-A injection resulted in a significant, dose-dependent reduction of OX-A induced grooming. In the circadian time model of male CD rats, SB-649868 treatment caused a dose-dependent reduction in sleep latency, with the maximal effect observed at 30mg/kg. SB-649868 at 10 and 30mg/kg also significantly increased total sleep time over the 5-hour testing period in a dose-dependent manner[3].
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