www.aasraw.com
How drug KML-29 (1380424-42-9) works as inhibitor Content 1.Whats KML29(1380424-42-9) ?......................................................................................... 1 2.How to Stock KML-29 (1380424-42-9)?.......................................................................... 3 3.How does KML-29 (1380424-42-9)work?........................................................................3 4.A Experience about KML-29(1380424-42-9).................................................................5 5.Where can i get more information?................................................................................. 7
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
1
aas35@aasraw.com
www.aasraw.com
, 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 Weight
549.4
Purity
>=98%
Formulation
A crystlline solid As supplied 2 years from the QC date provided on the
Shelf Life Certificate of Analysis,When stored properly
2
aas35@aasraw.com
www.aasraw.com
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
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 3
aas35@aasraw.com
www.aasraw.com
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 4
aas35@aasraw.com
www.aasraw.com
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.
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,
5
aas35@aasraw.com
www.aasraw.com
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 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: 6
aas35@aasraw.com
www.aasraw.com
These results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects.
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. Every effort has been made to ensure that the information provided by AASraw up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. AASraw information has been compiled for use by healthcare practitioners and consumers in the United States and therefore AASraw does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. AASraw’s drug information does not endorse drugs, diagnose patients or recommend therapy. AASraw’s drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given 7
aas35@aasraw.com
www.aasraw.com
drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. AASraw does not assume any responsibility for any aspect of healthcare administered with the aid of informationAASraw provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.
8
aas35@aasraw.com
www.aasraw.com
9
aas35@aasraw.com
www.aasraw.com
10
aas35@aasraw.com