The Dual FAAH/MAGL Inhibitor JZL195 Compare With MAGL Inhibitor JZL184
1. What is JZL195?
JZL195 ,1210004-12-8 is a potent and selective dual inhibitor of FAAH and monacylglycerol lipase (MAGL). JZL195 has greater anti-allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. JZL195 may have greater potential in alleviating neuropathic pain, compared to selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists.2. How does JZL195 work?
Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) mediate the hydrolysis of the endocannabinoids arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. JZL 195 is a potent inhibitor of both FAAH and MAGL (IC50s = 2 and 4 nM, respectively).1 It poorly inhibits neuropathy target esterase and ABHD6 and does not inhibit other brain serine hydrolases. JZL 195 displays time-dependent inhibition of FAAH and MAGL in vivo, consistent with a covalent mechanism of activation. The in vivo inhibitory actions of JZL 195(1210004-12-8) against FAAH and MAGL are comparable to those of the selective inhibitors PF-3845and JZL 184 , respectively.1 Through its inhibitory actions, JZL195 simultaneously augments brain levels of AEA and 2-AG, producing antinociceptive, cataleptic, and hypomotility effects like those produced by direct CB1 agonists.3. What is JZL195 effects
JZL195 effects,JZL195 and the cannabinoid receptor agonist WIN55212 produced dose-dependent reductions in CCI-induced mechanical and cold allodynia, plus side effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED50 at least four times less than that at which it produced side effects. By contrast, WIN55212 reduced allodynia and produce side effects with similar ED50s. The maximal anti-allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195-induced anti-allodynia was maintained during repeated treatment.4. JZL195 compare with JZL184
-Chemical characteristics
| Name | JZL195 | JZL184 |
| CAS | 1210004-12-8 | 1101854-58-3 |
| Synonyms: | JZL 195;4-nitrophenyl 4-(3-phenoxybenzyl)piperazine-1-carboxylate;4-[(3-Phenoxyphenyl)methyl]-1-piperazinecarboxylic acid 4-nitrophenyl ester | JZL 184;4-Nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)Methyl]-1-piperidinecarboxylate;4-[Bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester;1-Piperidinecarboxylic acid, 4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-, 4-nitrophenyl ester;4-[Bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester JZL 184;JZL 184 JZL184 JZL-184 |
| MF: | C24H23N3O5 | C27H24N2O9 |
| Molecular structure diagram |  |  |
| MW: | C24H23N3O5 | 520.48746 |
| Description | JZL195 is a potent dual inhibitor of Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), enzymes that degrade the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), the endogenous ligands for the cannabinoid G-protein coupled receptors CB1 and CB2. IC50 values are 2 nM for MAGL and 4 nM for FAAH. JZL195 has been shown to inhibit endocannabinoid hydrolysis and elevate 2-AG and AEA levels in vivo. | JZL184 is an irreversible inhibitor for monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG).[1] It displays high selectivity for MAGL over other brain serine hydrolases, including the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), thereby making it a useful tool for studying the effects of endogenous 2-AG signaling, in vivo. Administration of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related behavioral effects. |
| Manufacturer | www.aasraw.com | www.aasraw.com |
| Price | Inquiry | Inquiry |
| Package | Foil bag or Customization | Foil bag or Customization |
| Delivery | Within 12 hours in working day | Within 12 hours in working day |
- Effects
Endocannabinoids such as 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (AEA) are biologically active lipids that are involved in a number of synaptic processes including activation of cannabinoid receptors. Monoacylglycerol lipase (MAGL) is a serine hydrolase responsible for the hydrolysis of 2-AG to arachidonic acid and glycerol, thus terminating its biological function. JZL 184 is a potent and selective inhibitor of monoacylglycerol lipase (MAGL) that displays IC50 values of 8 nM and 4 µM for inhibition of MAGL and fatty acid amide hydrolase in mouse brain membranes, respectively.1 When administered to mice at 16 mg/kg, intraperitoneally, JZL 184 reduces MAGL activity by 85%, elevates brain 2-AG levels by 8-fold, and elicits analgesic activity in a variety of pain assays that qualitatively mimics direct central cannabinoid (CB1) agonists.The biological actions of the endocannabinoids anandamide and 2-arachidonoyl glycerol (2-AG) are terminated by enzymatic hydrolysis of these lipids via fatty acid amide hydrolase (FAAH ) and monoacylglycerol lipase (MAGL), respectively. While several selective FAAH inhibitors have been developed and characterized in vitro and in vivo, none of the initial MAGL blockers have shown adequate potency and specificity for in vivo applications.
The analgesic efficacy of cannabinoids in chronic pain models is limited by side-effects. It has been proposed that this might be overcome by using agents which indirectly activate the endocannabinoid system. We examined the analgesic and side-effect profile of the dual FAAH/MAGL inhibitor JZL195 in an inflammatory pain model. The effect of systemic injections of a range of doses of JZL195 and the pan-cannabinoid receptor agonist WIN55212 were performed 1 day following intraplantar injection of CFA in C57BL/6 mice. JZL195 and WIN55212 both reduced mechanical allodynia and thermal hyperalgesia, and produced catalepsy and sedation in a dose dependent manner. Unlike WIN55212, JZL195 effects reduced allodynia at doses below those at which side-effects were observed. The effects of JZL195 and WIN55212 were abolished by co-application with the CB1 antagonist AM251. The CB2 antagonist also reduced the JZL195 anti-allodynia, and reversed the WIN55212 anti-allodynia. The reduction in allodynia produced by JZL195 was greater than that produced individually by the FAAH and MAGL inhibitors, URB597 and JZL184. These findings suggest that JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.
Systemic administration of JZL195 or JZL184 reduced horizontal and vertical motor activity dose-dependently, and increased time spent in immobility. In contrast to JZL195, which decreased motor activity at all doses tested, JZL184 was effective only at the highest dose (30 mg/kg, p<0.05). The motor effects of both JZL compounds are also presented as time course over a 60 min period.
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