SB-334867

Biological Activity

SB-334867 has excellent selectivity for the orexin-1 receptor, blood-brain barrier permeability and shows in vivo activity following ip dosing. SB-334867-A is a non-peptide OX(1) selective receptor antagonist. PKb values are 7.2 and < 5 for inhibition of intracellular Ca2+ release in CHO cells expressing human OX1 and OX2 receptors respectively. SB-334867 blocks orexin-A induced grooming and feeding following systemic administration in vivo. SB-334867-A (OX1, pKB = 7.4; OX2, pKB = 5.7), devoid of appreciable affinity for either 5-HT2B (pKi < 5.3) or 5-HT2C (pKi < 5.4) receptors, provides the first definitive evidence that a central behavioural effect of orexin-A (grooming) is mediated by OX1 receptors.

Protocol

Cell Experiment
Cell lines
Preparation method
Concentrations
Incubation time

Animal Experiment
Animal models	Male and female Sprague–Dawley rats
Formulation	10% (w/v) Encapsin in sterile water
Dosages	30 mg/kg
Administration	i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

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 resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor.
Porter RA, et al. Bioorg Med Chem Lett. 2001 Jul 23;11(14):1907-10. PMID: 11459658.

SB-334867-A: the first selective orexin-1 receptor antagonist.
Smart D, et al. Br J Pharmacol. 2001 Mar;132(6):1179-82. PMID: 11250867.

Evidence that orexin-A-evoked grooming in the rat is mediated by orexin-1 (OX1) receptors, with downstream 5-HT2C receptor involvement.
Duxon MS, et al. Psychopharmacology (Berl). 2001 Jan 1;153(2):203-9. PMID: 11205420.

A selective orexin-1 receptor antagonist reduces food consumption in male and female rats.
Haynes AC, et al. Regul Pept. 2000 Dec 22;96(1-2):45-51. PMID: 11102651.