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How drug KML-29 works as inhibitor

HowdrugKML-29worksasinhibitor......................................................................................1
I.KML29 basic Characters:....................................................................................... 1
1.Whats KML29(1380424-42-9) ?............................................................................2
2.How to Stock KML-29 (1380424-42-9)?............................................................... 3
3.How does KML-29 (1380424-42-9)work?............................................................ 4
4.A Experience about KML-29(1380424-42-9)......................................................5
KEY RESULTS:.................................................................................................... 5
CONCLUSIONS AND IMPLICATIONS:.................................................................6
5.Where can i get more information?..................................................................... 7

I.KML29 basic Characters:

Name: KML29
CAS: 1380424-42-9
Molecular Formula: C24H21F6NO7
Molecular Weight: 549.42
Melt Point: 204-206°C
Storage Temp: Store at -20°C
Color: White crystalline solid

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1.Whats KML29(1380424-42-9) ?

KML29(1380424-42-9) is a potent and orally active monoacylglycerol lipase inhibitor

that targets MAGL active site with greatly improved selectivity (rat/mouse ABHD6
IC50 = 1.60/4.87; no inhibitory activity against human/rat/mouse fatty acid amide
hydrolase (FAAH) up to 50 μM). KML29(1380424-42-9) in vivo treatment results in a
selective upregulation of 2-arachidonoyl glycerol (2-AG), but not
N-arachidonoyl-ethanolamine (AEA) in mice (brain Emax ∼20 mg/kg p.o. or i.p.;

peripheral Emax ∼1 mg/kg p.o.) and rats (brain Emax ∼40 mg/kg i.p.).
KML29(1380424-42-9)reduces inflammatory and neuropathic nociceptive behaviour
in animal studies without cannabimimetic side effects seen with dual FAAH & MAGL,
chronic administration, however, leads to CB1 receptor desensitization as observed
with other MAGL inhibitors.

Formal name KML-29

CAS Number 1380424-42-9
Molecular C24H21F6NO7
Formula
549.4
Weight
Purity >=98%
Formulation A crystlline solid
As supplied 2 years from the QC date provided on the Certificate of
Shelf Life
Analysis,When stored properly

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2.How to Stock KML-29 (1380424-42-9)?

The following data is based on the product molecular weight 549.42. Batch specific
molecular weights may vary from batch to batch due to solvent of hydration, which
will affect the solvent volumes required to prepare stock solutions.

Concentration/Solvent Volume/Mass 1mg 5mg 10mg

1mM 1.82ml 9.1ml 18.2ml
5mM 0.36ml 1.82ml 3.64ml
10mM 0.18ml 0.91ml 1.82ml
50mM 0.04ml 0.18ml 0.36ml

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3.How does KML-29 (1380424-42-9)work?

we tested KML29(1380424-42-9) in murine inflammatory (i.e. carrageenan) and

sciatic nerve injury pain models, as well as the diclofenac-induced gastric
haemorrhage model. KML29(1380424-42-9) was also evaluated for cannabimimetic
effects, including measurements of locomotor activity, body temperature, catalepsy,
and cannabinoid interoceptive effects in the drug discrimination paradigm. 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).We get
the key results: KML29(1380424-42-9) attenuated carrageenan-induced paw
oedema and completely reversed carrageenan-induced mechanical allodynia. These
effects underwent tolerance after repeatedadministration of high-dose
KML29(1380424-42-9), which were accompanied by cannabinoid receptor 1 (CB1 )
receptor desensitization. Acute or repeated KML29(1380424-42-9) administration
increased 2-AG levels and concomitantly reduced arachidonic acid levels, but
without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29
partially reversed allodynia in the sciatic nerve injury model and completely
prevented diclofenac-induced gastric haemorrhages. CB1 and CB2 receptors played
differential rolesin these pharmacological effects of KML29(1380424-42-9). In
contrast, KML29 did not elicit cannabimimetic effects, including catalepsy,
hypothermia and hypomotility. Although KML29did not substitute for Δ(9)
-tetrahydrocannabinol (THC) in C57BL/6J mice, it fullyand dose-dependantly
substituted for AEA in fatty acid amide hydrolase (FAAH) (-/-) mice, consistent with
previous work showing that dual FAAH and MAGL inhibitionproduces THC-like
subjective effects.

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4.A Experience about KML-29(1380424-42-9)

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 (1380424-42-9)attenuated carrageenan-induced paw oedema and

completely reversed carrageenan-induced mechanical allodynia. These effects
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underwent tolerance after repeated administration of high-dose
KML29(1380424-42-9), 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. Furthermore, KML29(1380424-42-9)
partially reversed allodynia in the sciatic nerve injury model and completely
prevented diclofenac-induced gastric haemorrhages. CB1 and CB2 receptors played
differential roles in these pharmacological effects of KML29. In contrast, KML29
(1380424-42-9)did not elicit cannabimimetic effects, including catalepsy,
hypothermia and hypomotility. Although KML29 did not substitute for Δ(9)
-tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose-dependantly
substituted for AEA in fatty acid amide hydrolase (FAAH) (-/-) mice, consistent with
previous work showing that dual FAAH and MAGL inhibition produces THC-like
subjective effects.

CONCLUSIONS AND IMPLICATIONS:

These results indicate that KML29, a highly selective MAGL inhibitor, reduces
inflammatory and neuropathic nociceptive behaviour without occurrence of
cannabimimetic side effects.

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5.Where can i get more information?

Remember, keep this and all other medicines out of the reach of children, never
share your medicines with others, and use this medication only for the indication
prescribed.
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