Everything about JJKK-048

 

  1.JJKK-048 (1515855-97-6)
  2.JJKK-048 Biochem/physiol Actions
  3.JJKK-048 Applications?
  4.The Analysis Report of MAGL inhibitor JJKK-048 in vivo
  5.Buy JJKK-048 from Reliable JJKK-048 Suppliers online

 


 

 

JJKK 048 video

 

 


 

I.JJKK 048 basic Characters:

 

Name: JJKK 048
CAS:  1515855-97-6
Molecular Formula:  C23H22N4O5
Molecular Weight:  434.44
Melt Point:
Storage Temp: -20°C
Color: White solid

 


 

1. JJKK-048 (1515855-97-6)aasraw

 

JJKK-048 is an ultrapotent and highly selective inhibitors of monoacylglycerol lipase. JJKK-048 potently (IC50 < 0.4 nM) inhibited human and rodent MAGL. JJKK-048 displayed low cross-reactivity with other endocannabinoid targets. Monoacylglycerol lipase (MAGL) terminates the signaling function of the endocannabinoid, 2-arachidonoylglycerol (2-AG). During 2-AG hydrolysis, MAGL liberates arachidonic acid, feeding the principal substrate for the neuroinflammatory prostaglandins. In cancer cells, MAGL redirects lipid stores toward protumorigenic signaling lipids. Thus MAGL inhibitors may have great therapeutic potential.

 

TECHNICAL DATA Of JJKK-048
Product name JJKK-048
CAS number 1515855-97-6
Appearance Solid powder
Purity >98% (or refer to the Certificate of Analysis)
Shipping Condition Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility Soluble in DMSO, not in water
Shelf Life >2 years if stored properly
Drug Formulation This drug may be formulated in DMSO
Stock Solution Storage 0 – 4 C for short term (days to weeks), or -20 C for long term (months).

 


 

2. JJKK-048 Biochem/physiol Actionsaasraw

 

JJKK-048 is a cell penetrant ultrapotent and highly selective inhibitor of monoacylglycerol lipase (MAGL) that exhibits a low cross-reactivity with other endocannabinoid targets. JJKK-048 is an irreversible inhibitor that binds to the active site S122. A potent, highly selective monoacylglycerol lipase (MAGL) with IC50 of <0.4 nM against human and rodent MAGL; exhibits extremely high potency in inhibiting MAGL in the brain and peripheral tissues and maintains good selectivity over other serine hydrolases; remarkably increases mouse brain 2-AG levels without affecting AEA levels, induces antinociception and dose-dependent hypomotility and hypothermia but no catalepsy in vivo.

 


 

3. JJKK-048 Applicationsaasraw

 

JJKK-048 inhibits monoacylglycerol lipase by terminating signaling pathway of 2-arachidonoylglycerol in mouse brain and human melanoma cell proteome. JJKK-048 can be classified as a MAGL inhibitor that has therapeutic potential for the treatment of cancers.

 


 

4. The Analysis Report of MAGL inhibitor JJKK-048 in vivoaasraw

 

(1) Introduction

Endocannabinoids are lipid-structured signaling molecules that act as natural ligands for cannabinoid CB1 and CB2 receptors, which are also the targets of the psychoactive component of Cannabis sativa. The two most intensively studied endocannabinoids are 2-arachidonoylglycerol (2-AG) and anandamide (AEA). Generally, endocannabinoids are synthesized on demand from plasma membrane phospholipid precursors, and after exerting their effect by activating specific receptors, they are rapidly degraded by enzymatic activity. The principal brain endocannabinoid is 2-AG, which regulates central nervous system development and synaptic plasticity. Endocannabinoids also regulate cognition, emotional functions, and food intake, and are involved in several pathophysiological processes, including pain and neurodegenerative diseases. However, for therapeutic purposes, direct activation of cannabinoid receptors has proved to be challenging due to the side effects affecting cognition and motor control.
Monoacylglycerol lipase (MAGL) is a serine hydrolase that catalyzes the hydrolysis of monoacylglycerols to their corresponding fatty acids and glycerol. MAGL has been suggested to be the main hydrolase terminating 2-AG actions in the brain, accounting for ∼85% of total 2-AG hydrolysis at the bulk brain level. The remaining ∼15% has been attributed mainly to two α/β-hydrolase domain–containing proteins (ABHDs), ABHD6 and ABHD12. According to recent studies, in addition to regulating synaptic 2-AG signaling, MAGL has been demonstrated to play a key role in controlling brain eicosanoid production. Notably, MAGL-catalyzed hydrolysis of 2-AG liberates arachidonic acid to be used as a precursor for the production of neuroinflammatory prostaglandins. The pharmacological or genetic inactivation of MAGL has attenuated neuroinflammation and exerted neuroprotective effects in mouse models of neurodegenerative diseases. Moreover, MAGL contributes to cancer pathogenicity by providing free fatty acids for the production of tumor-promoting bioactive lipids, such as lysophosphatidic acid and prostaglandins. Thus, pharmacological inhibitors of MAGL may have great therapeutic potential both by locally enhancing 2-AG levels and by reducing arachidonic acid–derived lipid production.

 

JJKK-048, a benzodioxol derivative, has been found to a MAGL inhibitor that could probably be significant in anticancer and anti-inflammatory studies.

 

Several types of compounds have been reported to inhibit MAGL, but only a few compounds represent sufficient selectivity and potency enabling their use in vivo. Especially important is to achieve selectivity between MAGL and fatty acid amide hydrolase (FAAH), the primary enzyme responsible for the degradation of AEA, since dual inhibition of MAGL and FAAH have been demonstrated to induce behavioral effects similar to those achieved with direct CB1 receptor agonists, including catalepsy. The sulfhydryl reagent N-arachidonoylmaleimide and a carbamate compound biphenyl-3-ylcarbamic acid cyclohexyl ester (URB602)were among the first compounds showing activity in vivo, but their potency and MAGL selectivity were proved to be insufficient. More recently, the carbamate compounds 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) and its derivative 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d]dioxol-5-yl)(hydroxy)methyl) piperidine-1-carboxylate (KML29) were reported as selective MAGL inhibitors that increase brain 2-AG levels and display a more restricted set of behavioral effects when compared with the CB1 agonists or the dual MAGL and FAAH inhibitors. Carbamate-based inhibitors typically inactivate serine hydrolases by an irreversible covalent modification (carbamoylation) of the catalytic serine nucleophile.
We have characterized piperazine and piperidine triazole ureas as potent and selective inhibitors of MAGL (Aaltonen et al., 2013). Our work culminated in the synthesis of compound {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048), which in vitro is the most potent and MAGL-selective inhibitor currently available. In the present study, we extend our initial study by testing the in vivo effects of JJKK-048. We provide evidence that JJKK-048 exhibits extremely high potency in inhibiting MAGL in the brain and peripheral tissues and maintains good selectivity over other serine hydrolases. We observed that acute administration of JJKK-048 remarkably increased mouse brain 2-AG levels without affecting AEA levels. According to behavioral experiments, JJKK-048 induced antinociception and dose-dependent hypomotility and hypothermia but no catalepsy. Among these in vivo effects, only the antinociceptive effect of JJKK-048 was blocked by rimonabant, suggesting non-CB1-mediated effects of JJKK-048 in behavioral tests.

 

(2) Proposed Mechanism of MAGL Inhibition by JJKK-048

In competitive ABPP, JJKK-048 prevented TAMRA-fluorophosphonate (FP) labeling of the MAGL active site serine (S122), suggesting that the inhibitor probably targets this catalytic residue. Fast dilution of JJKK-048-treated MAGL preparation did not result in time-dependent drop of inhibitor potency, suggesting further that JJKK-048 (similarly to the established irreversibly acting inhibitor MAFP) inhibited MAGL in a covalent manner. We therefore propose that the triazole acts as the leaving group and that JJKK-048 binds to the active site S122, forming a carbamate adduct. A similar reaction mechanism has been proposed for the triazole compound SAR629. Despite extensive efforts, we could not unambiguously confirm the presence of the JJKK-048-MAGL adduct with a mass spectrometric approach (see Supplemental Results).
In functional autoradiography, JJKK-046 and JJKK-048 evoked the MAFP-mimicking and AM251-sensitive GTPγS-binding responses. This was not due to direct CB1R activation, as in membrane GTPγS-binding assays assessing direct CB1R agonism, these compounds showed no agonist activity at CB1R (or CB2R) at concentrations up to 10−5 M. Thus, the MAFP-mimicking CB1R activity was due to inhibition of 2-AG (but not arachidonoyl ethanolamide, anandamide [AEA]) hydrolysis (see below). Notably, JJKK-046 showed moderate CB1R antagonist activity at concentrations ≥10−6 M (Table S2), a finding likely explaining the relatively modest response for this compound in functional autoradiography.

 

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(3) JJKK-048 Exhibits Remarkable MAGL Selectivity

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of endocannabinoid levels in inhibitor-treated brain sections indicated that JJKK-046 and JJKK-048, when tested at 1 μM final concentration (i.e., ∼3,700- and ∼4,700-fold higher concentrations than their respective IC50 values for MAGL), selectively increased tissue levels of 2-AG but not those of AEA . However, tissue AEA levels were significantly elevated with 10−5 M JJKK-046. In the same experiment, SAR629 and AKU-005 elevated tissue levels of both 2-AG and AEA, as would be expected from their potent dual inhibitory action on MAGL and FAAH.
Activity assays using rat and human FAAH preparations revealed that the two inhibitors exhibited notable MAGL selectivity over FAAH (JJKK-046 > 1,200-fold, JJKK-048 > 13,000-fold) (Table 4). Activity assays with human ABHD6 indicated that JJKK-046 possessed moderate inhibitor activity toward human ABHD6 (hABHD6) (160-fold MAGL selectivity), whereas for JJKK-048, the MAGL/ABHD6 selectivity ratio was ∼630-fold (Table 4). When tested at concentrations up to 10−6 M, human ABHD12 was resistant to these inhibitors (Table 4). Collectively, these data indicate that JJKK-048 in particular shows remarkable selectivity for MAGL over the other endocannabinoid hydrolases.

 

(4) Discussion

During their existence, MAGL inhibitors have enabled functional investigation of 2-AG signaling pathways and revealed MAGL’s role in physiological and pathophysiological processes. Sufficient potency and selectivity over other enzymes are required from an inhibitor intended to be used in vivo. Especially important is to achieve selectivity between MAGL and FAAH to avoid CB1 agonist-like cataleptic behavior. Selective MAGL inhibitors would provide means to treat conditions where increased 2-AG activity would be beneficial, including pain and neurodegenerative diseases.

 

(5) Conclusions

Based on the present findings, JJKK-048 can be used to globally inactivate MAGL in both brain and peripheral tissues. JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting AEA levels. According to ABPP experiments, JJKK-048 remained selective over FAAH, and the only off-target in brain was ABHD6. JJKK-048 appeared to be an extremely potent MAGL inhibitor in vivo, exhibiting a slowly reversible mechanism of action. Our results showed that JJKK-048 promoted significant analgesia in the writhing test with the low dose that did not cause cannabimimetic side effects. A higher dose of JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hypothermia, but not catalepsy. Based on these observations, JJKK-048 provides a potent pharmacological tool for the further functional characterization of MAGL.

 


 

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