LEI-401
目录号 : GC60982
An NAPE-PLD inhibitor
Cas No.:2393840-15-6
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LEI-401 is an inhibitor of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD; IC50 = 0.86 ?M in HEK293T cell membranes expressing the recombinant human enzyme).1 It is selective for NAPE-PLD over human cannabinoid (CB) receptor 1 (CB1), CB2, type IVE phospholipase A2, monoacylglycerol lipase (MAGL), and diacylglycerol lipase α (DAGLα), as well as mouse DAGLα, DAGLβ, fatty acid amide hydrolase (FAAH), and α/β-hydrolase domain-containing protein 6 (ABHD6), at 10 ?M. LEI-401 (10 ?M) reduces levels of a variety of N-acylethanolamines (NAEs), including N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), and N-arachidonoylethanolamine , in Neuro2a cells. It impairs fear extinction in a cued fear conditioning test in mice when administered at a dose of 30 mg/kg.
1.Mock, E.D., Mustafa, M., Gunduz-Cinar, O., et al.Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in miceNat. Chem. Biol.16(6)667-675(2020)
| Cas No. | 2393840-15-6 | SDF | |
| Canonical SMILES | O=C(C1=NC(N2C[C@H](C3=CC=CC=C3)CCC2)=NC(N4C[C@@H](O)CC4)=C1)NCC5CC5 | ||
| 分子式 | C24H31N5O2 | 分子量 | 421.54 |
| 溶解度 | DMSO: 100 mg/mL (237.23 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.3723 mL | 11.8613 mL | 23.7225 mL |
| 5 mM | 0.4745 mL | 2.3723 mL | 4.7445 mL |
| 10 mM | 0.2372 mL | 1.1861 mL | 2.3723 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice
Nat Chem Biol 2020 Jun;16(6):667-675.PMID:32393901DOI:10.1038/s41589-020-0528-7.
N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.
Structure-Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
J Med Chem 2021 Jan 14;64(1):481-515.PMID:33382264DOI:10.1021/acs.jmedchem.0c01441.
N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of N-acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (1, LEI-401) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [Mock Nat Chem. Biol., 2020, 16, 667-675]. Here, we describe the structure-activity relationship (SAR) of a library of pyrimidine-4-carboxamides as inhibitors of NAPE-PLD that led to the identification of LEI-401. A high-throughput screening hit was modified at three different substituents to optimize its potency and lipophilicity. Conformational restriction of an N-methylphenethylamine group by replacement with an (S)-3-phenylpiperidine increased the inhibitory potency 3-fold. Exchange of a morpholine substituent for an (S)-3-hydroxypyrrolidine reduced the lipophilicity and further increased activity by 10-fold, affording LEI-401 as a nanomolar potent inhibitor with drug-like properties. LEI-401 is a suitable pharmacological tool compound to investigate NAPE-PLD function in vitro and in vivo.