Selective monoacylglycerol lipase inhibitors: antinociceptive versus cannabimimetic effects in mice

The Journal of Pharmacology and Experimental Therapeutics
B M Ignatowska-JankowskaAron H Lichtman

Abstract

The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) plays an important role in a variety of physiologic processes, but its rapid breakdown by monoacylglycerol lipase (MAGL) results in short-lived actions. Initial MAGL inhibitors were limited by poor selectivity and low potency. In this study, we tested JZL184 [4-nitrophenyl 4-[bis(2H-1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate] and MJN110 [2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate], MAGL inhibitors that possess increased selectivity and potency, in mouse behavioral assays of neuropathic pain [chronic constriction injury (CCI) of the sciatic nerve], interoceptive cannabimimetic effects (drug-discrimination paradigm), and locomotor activity in an open field test. MJN110 (1.25 and 2.5 mg/kg) and JZL184 (16 and 40 mg/kg) significantly elevated 2-AG and decreased arachidonic acid but did not affect anandamide in whole brains. Both MAGL inhibitors significantly reduced CCI-induced mechanical allodynia with the following potencies [ED50 (95% confidence limit [CL]) values in mg/kg: MJN110 (0.43 [0.30-0.63]) > JZL184 (17.8 [11.6-27.4])] and also substituted for the potent cannabinoid receptor agonist CP55,940 [2-[(1R,2R,5R)-5-h...Continue Reading

References

Nov 24, 1976·Psychopharmacology·M A EvansR B Forney
Mar 24, 1995·European Journal of Pharmacology·J WileyB Martin
Mar 1, 1996·Pharmacology, Biochemistry, and Behavior·I S McGregorG Prior
Mar 10, 1999·Perception & Psychophysics·B Treutwein, H Strasburger
Jun 17, 1999·Lancet·C J Woolf, R J Mannion
Feb 21, 2002·Proceedings of the National Academy of Sciences of the United States of America·Carolina García-MartinezAntonio Ferrer-Montiel
Jul 24, 2002·Proceedings of the National Academy of Sciences of the United States of America·T P DinhD Piomelli
Jun 24, 2005·Nature·Andrea G HohmannDaniele Piomelli
Aug 24, 2005·Nature Neuroscience·Judit K MakaraDaniele Piomelli
Dec 5, 2006·British Journal of Pharmacology·S VandevoordeC J Fowler
Dec 22, 2007·Chemistry & Biology·Jacqueline L BlankmanBenjamin F Cravatt
Nov 26, 2008·Nature Chemical Biology·Jonathan Z LongBenjamin F Cravatt
Apr 30, 2009·Annual Review of Neuroscience·Michael CostiganClifford J Woolf
Jun 9, 2009·The Journal of Pharmacology and Experimental Therapeutics·S G KinseyA H Lichtman
Nov 18, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jonathan Z LongBenjamin F Cravatt
Jun 18, 2010·The Journal of Pain : Official Journal of the American Pain Society·Steven G KinseyAron H Lichtman
Aug 24, 2010·Nature Neuroscience·Joel E SchlosburgBenjamin F Cravatt
Jan 5, 2011·British Journal of Pharmacology·Josée GuindonAndrea G Hohmann
Jul 2, 2011·The Journal of Pharmacology and Experimental Therapeutics·Divya RameshAron H Lichtman
Feb 2, 2012·Nature Reviews. Drug Discovery·Sarah Nightingale
Oct 24, 2012·International Journal of Medical Sciences·Hiroko UranoB Yukihiro Hiraoka
Jun 5, 2013·ACS Chemical Neuroscience·Micah J NiphakisBenjamin F Cravatt
May 27, 2014·European Journal of Pharmacology·Jenny L WileyRobert E Vann

❮ Previous
Next ❯

Citations

Jun 12, 2016·Chemico-biological Interactions·Daniela T Longhi-BalbinotWaldiceu A Verri
Jun 20, 2017·Neuropharmacology·Stephen G WoodhamsVolker Neugebauer
Sep 1, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Giulia DonvitoAron H Lichtman
Oct 4, 2017·The Journal of Pharmacology and Experimental Therapeutics·Jenny L WilkersonAron H Lichtman
Oct 12, 2018·The Journal of Pharmacology and Experimental Therapeutics·Jason R ClapperJacqueline L Blankman
Jul 8, 2016·Behavioural Pharmacology·Jenny L WileyAron H Lichtman
Feb 15, 2020·The Journal of Pharmacology and Experimental Therapeutics·A L ThompsonT W Vanderah
Nov 12, 2019·British Journal of Pharmacology·Stephen P H AlexanderUNKNOWN CGTP Collaborators
Jun 6, 2018·Frontiers in Systems Neuroscience·Dale E Bjorling, Zun-Yi Wang
Jan 23, 2016·The Journal of Pharmacology and Experimental Therapeutics·Jenny L WilkersonAron H Lichtman
Aug 9, 2016·British Journal of Pharmacology·James J BurstonVictoria Chapman
Jun 27, 2019·The Journal of Pharmacology and Experimental Therapeutics·Jenny L WilkersonLance R McMahon
Aug 3, 2019·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Ian R JacobsSylvia Fitting
Dec 31, 2015·Chembiochem : a European Journal of Chemical Biology·Carina DolerRolf Breinbauer
Feb 16, 2021·Neuroscience Letters·Barkha J Yadav-Samudrala, Sylvia Fitting
Mar 20, 2021·Experimental Neurology·Douglas J HermesSylvia Fitting
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aoife M ThorntonMichelle Roche
Nov 18, 2017·Journal of Medicinal Chemistry·Christopher R ButlerMichael A Brodney

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.