JZL-184

Details

Stereochemistry	ACHIRAL
Molecular Formula	C27H24N2O9
Molecular Weight	520.4875
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(C1CCN(CC1)C(=O)OC2=CC=C(C=C2)[N+]([O-])=O)(C3=CC=C4OCOC4=C3)C5=CC=C6OCOC6=C5

InChI

InChIKey=SEGYOKHGGFKMCX-UHFFFAOYSA-N

InChI=1S/C27H24N2O9/c30-26(38-21-5-3-20(4-6-21)29(32)33)28-11-9-17(10-12-28)27(31,18-1-7-22-24(13-18)36-15-34-22)19-2-8-23-25(14-19)37-16-35-23/h1-8,13-14,17,31H,9-12,15-16H2

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19029917
Curator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/21600985 | http://www.ncbi.nlm.nih.gov/pubmed/23127915

JZL184 is an irreversible inhibitor for monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG). Selectivity of JZL 184 over other serine hydrolases makes it useful compound to study endogenous 2-AG signaling. Administration of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related behavioral effects. JZL184 was found effective in preclinical models of anxiety and chemotherapy-induced neuropathic pain.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Monoglyceride lipase 8 Target ID: CHEMBL4191 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19029917	Inhibitor 8504		8.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Neuropathic pain 26 Sources: http://www.ncbi.nlm.nih.gov/pubmed/23127915	Palliative		Preclinical	Unknown Approved Use Unknown
Anxiety 275 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21600985	Primary		Preclinical	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
Endogenous 2-Arachidonoylglycerol Alleviates Cyclooxygenases-2 Elevation-Mediated Neuronal Injury From SO2 Inhalation via PPARγ Pathway.	2015-10	26209559
Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates.	2012-05-25	22542104
Effect of developmental chlorpyrifos exposure, on endocannabinoid metabolizing enzymes, in the brain of juvenile rats.	2011-07	21507991
Inactivation of lipid glyceryl ester metabolism in human THP1 monocytes/macrophages by activated organophosphorus insecticides: role of carboxylesterases 1 and 2.	2010-12-20	21049984
Inhibitors of monoacylglycerol lipase, fatty-acid amide hydrolase and endocannabinoid transport differentially suppress capsaicin-induced behavioral sensitization through peripheral endocannabinoid mechanisms.	2010-09	20416378
High-performance liquid chromatography assay with fluorescence detection for the evaluation of inhibitors against human recombinant monoacylglycerol lipase.	2010-04-15	20015447
Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.	2009-01	19029917

Patents

Sample Use Guides

In Vivo Use Guide

JZL184 was dissolved by vortexing, sonicating, and gentle heating directly into 4:1 v/v PEG300:Tween80 (10, 4, 2, or 1 mg ml-1). Male C57Bl/6J mice (6-8 weeks old, 20-26 g) were intraperitoneally (i.p.) administered JZL184 at a volume of 4 ul g-1 weight (40, 16, 8, or 4 mg kg-1 by the dilutions above).

Route of Administration: Intraperitoneal

In Vitro Use Guide

Recombinant MAGL in COS7 cells (0.1 µg) in PBS (200 µl) was incubated with inhibitor at 37C for 30 min. 2-AG (100 µM) was added. Reaction was quenched by the addition of 500 µL 2:1 v/v CHCl3:MeOH, doped with 0.5 nmol PDA, vortexed, then centrifuged (1,400 x g, 3 min) to separate the phases. 30 µl of the resultant organic phase was injected onto an Agilent 1100 series LC-MSD SL instrument. Hydrolysis products were quantified by measuring the area under the peak in comparison to the PDA standard.

Name

Type

Language

JZL-184

Common Name

English

1-PIPERIDINECARBOXYLIC ACID, 4-(BIS(1,3-BENZODIOXOL-5-YL)HYDROXYMETHYL)-, 4-NITROPHENYL ESTER

Preferred Name

English

Code System Code Type Description

WIKIPEDIA

JZL184