KML29, known for its high selectivity, oral activity, and irreversible inhibition of MAGL, showcases IC50 values of 15 nM, 43 nM, and 5.9 nM for mouse, rat, and human MAGL respectively. This inhibitor has minimal cross-reactivity towards other central and peripheral serine hydrolases, including an absence of detectable activity against FAAH[1].[2].
体内研究
Administered at 20 mg/kg, KML29 displays a significant yet modest protective effect against LPS-induced fever[3].
体外研究
KML29 dose-dependently elevates brain levels of 2-AG up to 10-fold without affecting the brain levels of anandamide, palmitoylethanolamide, and oleoylethanolamide[2].
KML29 efficiently inhibits 2-AG hydrolysis without impacting AEA hydrolysis at any tested concentration[2].
KML29 细胞实验
Cell Line
Concentration
Treated Time
Description
References
rat cortical primary neurons
250 nM
from DIV6 to DIV12, every 48 hours
To evaluate the effect of MAGL inhibition on neuronal survival. KML29 significantly increased the risk of neuronal death in neuron-enriched cultures lacking glial cells, while neuronal survival was unaffected in mixed cultures (containing glial cells).
Biomolecules. 2020 Aug 18;10(8):1198
PL neurons
100nM
10 minutes
KML29 augmented evoked excitatory neurotransmission as evidenced by a left-shift in fEPSP I/O curve, and decreased sIPSC amplitude. KML29 also altered intrinsic properties of PL neurons including depolarization of resting membrane potential, decreased membrane time constant and decreased instantaneous frequency.
Neuropharmacology. 2020 Apr;166:107964
KML29 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Sprague-Dawley rats
Ischemic injury model
Intravenous injection
1 mg/kg
Once daily for three days
To evaluate the neuroprotective effects of KML29 in an ischemic injury model. Results showed that KML29 treatment significantly improved neuronal protection in the striatum and reduced neuroinflammation.
Theranostics. 2021 Sep 13;11(19):9492-9502
C57BL/6 J mice
Chronic constriction injury (CCI) model of neuropathic pain
Intraperitoneal injection
1–40 mg/kg
Once daily for 7 days
To evaluate the analgesic effects of KML29 in combination with gabapentin. Results showed that low-dose KML29 combined with gabapentin additively attenuated mechanical allodynia and synergistically reduced cold allodynia without inducing tolerance.
Br J Pharmacol. 2017 Dec;174(23):4523-4539
Mice
Inflammatory and neuropathic pain models
Intraperitoneal injection
40 mg·kg−1
Single or repeated administration
KML29 significantly 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 CB1 receptor desensitization. KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenac-induced gastric haemorrhages.
Br J Pharmacol. 2014 Mar;171(6):1392-407
Rats
Predator-induced fear model
Intraperitoneal injection
4 and 16 mg/kg
Single administration, 4 hours before testing
KML29 produced a dose-dependent anxiolytic-like effect in TMT-exposed rats, increasing open arm time and reducing the anxiety index.
Neuropsychopharmacology. 2020 Jul;45(8):1330-1338
Male Wistar rats
Monoiodoacetate (MIA)-induced osteoarthritis pain model
Intra-articular injection
700 μg/50μl
Single administration, observed for 240 minutes
To evaluate the effect of KML29 on MIA-induced secondary allodynia. Results showed that KML29 significantly improved the hindpaw withdrawal threshold, and this analgesic effect was blocked by CB1R and CB2R antagonists.
Arthritis Res Ther. 2020 Jan 14;22(1):9
Mice
Normotensive murine model
Topical application
1 mM
Measured at 1, 4, and 8 hours post-treatment
KML29 lowers IOP in a CB1 receptor-dependent manner
Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):3287-96
Rats
Object recognition task
Bilateral intra-CA1 hippocampal injections
2 ng or 20 ng
Immediately after training, tested 1 hr later
KML29 abolished the impairing effects of stress on short-term memory, improving short-term recognition memory performance
Int J Mol Sci. 2020 Oct 3;21(19):7316
Rat
Healthy rats
In vitro
1 µM
1 hour
KML29 significantly reduced MAGL activity, by 92% in TG, 88% in cDRG, 86% in tDRG, and 93% in lDRG.
Intra-vmPFC administration of KML29 prior to stress prevented stress-induced anxiety, while systemic administration of KML29 exacerbated stress-induced anxiety.
Neuropharmacology. 2020 Apr;166:107964
Mice
Acute N-methyl-D-aspartate (NMDA) receptor hypofunction model
Intraperitoneal injection
1, 5, 20, 40 mg/kg
Single administration
To evaluate the impact of KML-29 on long-term memory in mice, results showed that KML-29 significantly increased the LI values for memory acquisition at the highest dose (40 mg/kg), and at the two highest doses (20 and 40 mg/kg) for memory consolidation and retrieval stages.
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