SB-649868 is a selective orally active orexin (OX) receptor antagonist with pKi values of 9.4 and 9.5 at the OX1 and OX2 receptor, respectively. SB-649868 antagonizes orexin-A-induced inositol 1 phosphate (IP1) accumulation with the following pKB 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. 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).
Cell Experiment | |
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Cell lines | Chinese Hamster Ovary (CHO) cells |
Preparation method | Chinese Hamster Ovary (CHO) cells stably transfected with human OX1 orexin receptor are cultured in Dulbecco's modified Eagle's medium F12 Ham, supplemented with 10% fetal bovine serum (FBS), 2 mg/mL glutamine, 600 μg/ml geneticin at 37 °C in an atmosphere of 95% air and 5% CO2. CHO cells stably transfected with human OX2 orexin receptor are cultured in alpha-MEM supplemented with 10% FBS, 100 units/mL penicillin G, 100 units/mL streptomycin and 400 μg/mL geneticin, at 37 °C in an atmosphere of 95% air and 5% CO2. Accumulation of IP1 is measured using IP-One HTRF terbium cryptate-based assay. OX1-CHO cells are seeded into white 384-well plate at the cell density of 1×104 cells per well and cultured for 24 h in the presence of 5 mM sodium butyrate while OX2-CHO cells are seeded at the cell density of 4×104 cells per well and cultured for 24 h in culture medium. After washings Hank's Balanced Salt Solution (HBSS) at room temperature containing 20 mM HEPES pH 7.4, 50 mM, LiCl and 0.1% Bovine Serum Albumin (BSA) cells are pre-incubated for 45 min with antagonist and then treated with agonist for 60 min at 37 °C. Detection reagents, IP1-d2 tracer and anti-IP1-cryptate are diluted in lysis buffer and added to the cells. Following 60 min incubation at room temperature, time-resolved fluorescence at 615 nm and 665 nm are measured with Envision Multilabel flash lamp reader with 100 flashes and 400 μs integration time. |
Concentrations | final DMSO concentration not exceeding 0.5% for functional studies and 1% for binding studies |
Incubation time | 45 min |
Animal Experiment | |
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Animal models | |
Formulation | |
Dosages | |
Administration |
Molecular Weight | 477.55 |
Formula | C26H24FN3O3S |
CAS Number | 380899-24-1 |
Solubility (25°C) | DMSO 10 mM |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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