KML-29 - CAS 1380424-42-9
Catalog number: 1380424-42-9
Category: Inhibitor
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KML-29, a effective MAGL inhibitor, has been found to have probable effect against neuropathic pain. IC50: 15, 43, and 5.9 nM (mouse, rat, and human brain proteomes).
10 mM in DMSO
-20ºC Freeze
KML-29 is a effective MAGL inhibitor that has been found to have probable effect against neuropathic pain.
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As supplied, 2 years from the QC date provided on the Certificate of Analysis, when stored properly
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1.Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model.
Miller S;Leishman E;Hu SS;Elghouche A;Daily L;Murataeva N;Bradshaw H;Straiker A Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):3287-96. doi: 10.1167/iovs.16-19356.
PURPOSE: ;Cannabinoids, such as Δ9-THC, act through an endogenous signaling system in the vertebrate eye that reduces IOP via CB1 receptors. Endogenous cannabinoid (eCB) ligand, 2-arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic potential of harnessing eCBs to lower IOP.;METHODS: ;We tested the effect of topical application of 2-AG and MAGL blockers in normotensive mice and examined changes in eCB-related lipid species in the eyes and spinal cord of MAGL knockout (MAGL-/-) mice using high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). We also examined the protein distribution of MAGL in the mouse anterior chamber.;RESULTS: ;2-Arachidonoyl glycerol reliably lowered IOP in a CB1- and concentration-dependent manner. Monoacylglycerol lipase is expressed prominently in nonpigmented ciliary epithelium. The MAGL blocker KML29, but not JZL184, lowered IOP. The ability of CB1 to lower IOP is not desensitized in MAGL-/- mice. Ocular monoacylglycerols, including 2-AG, are elevated in MAGL-/- mice but, in contrast to the spinal cord, arachidonic acid and prostaglandins are not changed.
2.In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects.
Ignatowska-Jankowska BM;Ghosh S;Crowe MS;Kinsey SG;Niphakis MJ;Abdullah RA;Tao Q;O' Neal ST;Walentiny DM;Wiley JL;Cravatt BF;Lichtman AH Br J Pharmacol. 2014 Mar;171(6):1392-407. doi: 10.1111/bph.12298.
BACKGROUND AND PURPOSE: ;Since monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), a great need has emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate).;EXPERIMENTAL APPROACH: ;In the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac-induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm.;KEY RESULTS: ;KML29 attenuated carrageenan-induced paw oedema and completely reversed carrageenan-induced mechanical allodynia. These effects underwent tolerance after repeated administration of high-dose KML29, which were accompanied by cannabinoid receptor 1 (CB1 ) receptor desensitization. Acute or repeated KML29 administration increased 2-AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain.
3.Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS.
Pasquarelli N;Engelskirchen M;Hanselmann J;Endres S;Porazik C;Bayer H;Buck E;Karsak M;Weydt P;Ferger B;Witting A Neuropharmacology. 2017 Sep 15;124:157-169. doi: 10.1016/j.neuropharm.2017.03.037. Epub 2017 Mar 31.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points. The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration. Whether this is a defense mechanism or part of the pathogenesis remains to be determined. The neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL), accumulates in the spinal cords of transgenic models of ALS. We tested the hypothesis that this 2-AG increase is a protective response in the low-copy SOD1;G93A; mouse model of ALS. We show that oral application of the MAGL inhibitor KML29 delays disease onset, progression and survival. Furthermore, we could demonstrate that KML29 reduced proinflammatory cytokines and increased brain-derived neurotrophic factor (BDNF) expression levels in the spinal cord, the major site of neurodegeneration in ALS.
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CAS 1380424-42-9 KML-29

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