Research Area
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Description
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Cancer |
Biological Activity
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Description
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URB597 (KDS-4103) is a potent FAAH inhibitor with IC50 of 4.6 nM. |
Targets
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FAAH |
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IC50 |
4.6 nM [1] |
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In Vitro
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URB597 binds in the hydrophobic pocket and catalytic core of FAAH that connects the active site residues to the membrane surface of FAAH. [1] URB597 inhibits FAAH activity in human liver microsomes with IC50 of 3 nM. [2] URB597 reduces the expression of the LPS-induced enzymes cyclo-oxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS; NOS2) in primary rat microglial cell, with a concomitant reduction in the release of the inflammatory mediators prostaglandin E2 (PGE2) and (NO) nitric oxide. [3] URB597 evokes Ca2+ entry in HEK293-F Cells transiently expressing human or rat TRPA1 gene. URB597 also activates Ca2+ entry in rat DRG neurons natively expressed TRPA1 channels. [4] |
In Vivo
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URB597 inhibits [3H]anandamide hydrolysis in rat brain membranes with a parallel increase in brain anandamide, OEA, and PEA content by inhibition of FAAH. URB597 enhances the hypothermia effect induced by ethanolamide by inhibiting FAAH. [5] When delivered intraperitonealy (0.3 mg/kg) URB597 reduces allodynia and hyperalgesia through cannabinoid CB1 and CB2 receptor-mediated analgesia in rats with inflammatory pain. [6] URB597 reduces the reduction in body weight gain and sucrose intake induced by the chronic mild stress in rats through inhibition of brain FAAH activity. [7] URB597 could reverse most depressive-like symptoms induced by adolescent THC exposure in femal rats. [8] |
Clinical Trials
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Features
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Protocol
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Kinase Assay
[1]
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Pharmacology |
Membrane fractions are prepared from brain homogenates, and FAAH activity is assayed using [3H]anandamide (anandamide[ethanolamine-3H], 60 Ci/mmol) as a substrate. Rat brain membranes (50 μg protein) are incubated for 30 min at 37 °C in buffer containing [3H]anandamide and varying concentrations of URB597. At the end of the incubation period, we stopp the reactions with a mixture of chloroform/methanol and measured [3H]ethanolamine in the aqueous phase by liquid scintillation counting. |
Animal Study
[5]
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Animal Models |
Adult male Wistar rats (250–300 g) and C57/BL6 or FAAH-/- mice |
Formulation |
sterile 0.9% sodium chloride solution |
Doses |
0.3 mg/kg |
Administration |
Inject subcutaneously in a single dose 2 hours or 16 hours before killing |
References |
[1] Mor M, et al. J Med Chem, 2004, 47(21), 4998-5008.
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[2] Piomelli D, et al. CNS Drug Rev, 2006, 12(1), 21-38.
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[3] Tham CS, et al. FEBS Lett, 2007, 581(16), 2899-2904.
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[4] Niforatos W, et al. Mol Pharmacol, 2007, 71(5), 1209-1216.
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[5] Fegley D, et al. J Pharmacol Exp Ther, 2005, 313(1), 352-358.
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[6] Jayamanne A, et al. Br J Pharmacol, 2006, 147(3), 281-288.
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[7] Bortolato M, et al. Biol Psychiatry, 2007, 62(10), 1103-1110.
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[8] Realini N, et al. Neuropharmacology, 2011, 60(2-3), 235-243.
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