Fatty acid amide hydrolase (FAAH), an integral membrane bound enzyme, are intracellular enzymes responsible for the hydrolysis of endogenous fatty acid ethanolamides (FAEs). URB-597 (KDS-4103) is FAAH inhibitor with IC50 of 4.6 nM without effect on other cannabinoid-related targets[3]. Treatment with 10 μM URB-597 in microglial cells reduced the release of PGE2 to approximately 50% of control, and inhibited LPS stimulated TNF and NO release and iNOS expression[4]. In vivo, URB-597 (0.3 mg/kg/day, intraperitoneal (i.p.) injection) treatment in chronic cerebral hypoperfusion model inhibited impaired autophagy degradation and the disruption of beclin-1/Bcl-2 complex and subsequently cut off BNIP3-cyt C- and parkin-required mitophagy, finally preventing the abnormal excessive autophagy and mitophagy[5].
作用机制
Carbamoyl group in URB-597 may form two distinct hydrogen bonds with FAAH: one as an acceptor, with the hydroxyl group of Thr488, and the other as a donor, with the main chain carbonyl group of Leu192.
URB-597 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rhesus monkeys
Drug discrimination assays
Intravenous injection
0.32-3.2 mg/kg
Single or multiple dosing
To examine the behavioral effects of URB-597 alone and in combination with anandamide. URB-597 markedly enhanced the behavioral effects of anandamide but did not share effects with exogenous anandamide when administered alone.
Br J Pharmacol. 2011 Sep;164(2b):655-66
Mice
Schizophrenia-like model
Intraperitoneal injection
0.1, 0.3, 1 mg/kg
Acute administration
Evaluate the effects of URB-597 on MK-801-induced schizophrenia-like symptoms in mice. Results showed that URB-597 at 0.3 mg/kg attenuated MK-801 (0.6 mg/kg)-induced memory impairment, while at 1 mg/kg it potentiated MK-801 (0.3 mg/kg)-induced memory impairment.
Mol Neurobiol. 2019 Nov;56(11):7251-7266
Rats
Subchronic PCP model of schizophrenia
Intraperitoneal injection
0.3 mg/kg
Single dose or for 7 days
URB-597, by inhibiting FAAH to increase endocannabinoid levels, reversed aberrant dopamine neuron activity in PCP-treated rats.
Int J Neuropsychopharmacol. 2014 Oct 31;18(1):pyu035
Mice
Elevated Plus Maze test
Intraperitoneal injection
0.1, 0.3, 1 mg/kg
Single administration, observed after 30 minutes
Evaluate the effect of URB-597 on anxiety-like behavior in mice, results showed anxiolytic effect at 0.3 mg/kg dose
Molecules. 2025 Feb 13;30(4):867
Rat
Aged rat model
Subcutaneous injection
1 mg/kg
Every second day for 28 days
Chronic URB 597 treatment prevented the age-related reduction in NICD and Nct expression in the cortex of aged rats, restoring the Notch-1 signaling pathway.
J Biol Chem. 2012 Oct 5;287(41):34709-21
Mice
Chronic social defeat stress model
Intraperitoneal injection
1 mg/kg
Once daily for 21 days
URB-597 significantly reduced depression-like behavior and increased social interaction behavior compared to CB1 inhibitor
Germany
... 展开 >> Dep. of Psychiatry and Psychotherapy, Central Institute of Mental Health
Not yet recruiting
Mannheim, BW, Germany, 68159
Contact: F. Markus Leweke, MD +49 621 1703 ext 2321 leweke@cimh.de
Contact: Cathrin Rohleder, PhD +49 621 1703 ext 2333 rohleder@cimh.de
Sub-Investigator: J. Malte Bumb, MD
Sub-Investigator: Cathrin Rohleder, PhD
Sub-Investigator: Till van der List, MD
Sub-Investigator: Juliane K. Mueller, MD
Sub-Investigator: Frank Enning, MD 收起 <<
Germany
... 展开 >> Dep. of Psychiatry and Psychotherapy, Central Institute of Mental Health
Not yet recruiting
Mannheim, BW, Germany, 68159
Contact: F. Markus Leweke, MD +49 621 1703 ext 2321 leweke@cimh.de
Contact: Cathrin Rohleder, PhD +49 621 1703 ext 2333 rohleder@cimh.de
Sub-Investigator: J. Malte Bumb, MD
Sub-Investigator: Cathrin Rohleder, PhD
Sub-Investigator: Till van der List, MD
Sub-Investigator: Juliane K. Mueller, MD
Sub-Investigator: Frank Enning, MD 收起 <<
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