SB-649868 is a potent and selective orally active orexin (OX) 1 and OX₂ receptor antagonist (pK_i =9.4 and 9.5 at the OX₁ and OX₂ receptor, respectively). IC50 & Target: pKi: 9.4 (OX₁), 9.5 (OX₂)^[1] In Vitro: SB-649868 is identified as one the most in vitro potent dual OX₁ and OX₂ receptor antagonist known at that time (pK_i=9.4 and 9.5 at the OX₁ and OX₂ receptor, respectively) ^[1]. SB-649868 antagonizes orexin-A-induced inositol 1 phosphate (IP1) accumulation with the following pK_B value (OX₁=9.67; OX₂=9.64). SB-649868 displaces the [³H]ACT-078573 receptor binding with the following pKi values: OX₁=9.27; OX₂=8.91. Increasing concentrations of SB-649868 (0.3 nM-30 nM) induces a rightward shift of the orexin-A CRCs with a depression of the agonist efficacy suggesting a clear non-surmountable behavior. The calculated apparent pK_b values are 9.67±0.03 and 9.64±0.07 for OX₁ and OX₂^[2]. In Vivo: Pharmacokinetic studies in the male CD rat, performed at 1 mg/kg, iv and 3 mg/kg, po, demonstrate an excellent pharmacokinetic profile for a hypnotic agent featuring moderate clearance in plasma (Cl_p=24 mL/min/kg), short half-life of (<0.6 h) and a low volume of distribution (V_ss=1.1 l/kg), coupled with excellent oral bioavailability (F=85%) and good exposure in plasma (C_max=333 ng/mL). A brain to blood ratio (B/B) of 0.1:1 is observed 1 h after iv administration, a value in line with the expected partition between the two compartments based on the lower tissue binding observed in vitro in brain tissues (fraction unbound/brain=5.28%) with respect to plasma proteins (fraction unbound/plasma=1.34%). SB-649868, administered orally 3 h before OX-A injection at doses of 1, 3 and 10 mg/kg, causes a dose-dependent reduction of OX-A induced grooming as measured by total time spent grooming and number of grooming bouts (p <0.01 at 3 and 10 mg/kg po) ^[1]. From dissociation kinetic studies using [³H]ACT-078573, the calculated long half-life, (t_1/2) supports the non-surmountability profile of SB-649868 (t_1/2=35.91 min) at OX₁ orexin receptor. The long or moderately long t_1/2values for SB-649868 at OX₂ orexin receptor (t_1/2=8.09 min)^[2].