LY-2940094
(Synonyms: BTRX-246040) 目录号 : GC36508
LY-2940094 是一种口服有效的选择性 nociceptin 受体 (NOP 受体) 拮抗剂，对 NOP 受体具有高亲和力(Ki 为 0.105 nM) 和拮抗活力 (Kb=0.166 nM)。LY-2940094 可降低动物模型的自身给药酒精依赖。
Cas No.:1307245-86-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LY-2940094 is a potent, selective and orally available nociceptin receptor (NOP receptor) antagonist with high affinity (Ki=0.105 nM) and antagonist potency (Kb=0.166 nM). LY-2940094 reduces ethanol self-administration in animal models[1]. Ki: 0.105 nM (NOP receptor)[1]Kb: 0.166 nM (NOP receptor)[1]
LY-2940094 (LY2940094; 3, 10, or 30 mg/kg; 2-3 mL/kg; orally daily; for 4 days) dose-dependently reduces homecage ethanol self-administration in Indiana Alcohol-Preferring (P) and Marchigian Sardinian Alcohol-Preferring (msP) rats, without affecting food/water intake or locomotor activity[1]. Animal Model: Female Alcohol-Preferring (P) rats (250-320 g); Male Marchigian Sardinian Alcohol-Preferring (msP) rats (400-450 g)[1]
[1]. Rorick-Kehn LM, et al. A Novel, Orally Bioavailable Nociceptin Receptor Antagonist, LY2940094, Reduces Ethanol Self-Administration and Ethanol Seeking in Animal Models. Alcohol Clin Exp Res. 2016 May;40(5):945-54.
| Cas No. | 1307245-86-8 | SDF | |
| 别名 | BTRX-246040 | ||
| Canonical SMILES | OCC1=CC=CN=C1N2N=C(C)C(CN3CCC4(C5=C(C=C(Cl)S5)C(F)(F)CO4)CC3)=C2 | ||
| 分子式 | C22H23ClF2N4O2S | 分子量 | 480.96 |
| 溶解度 | DMSO: 41.67 mg/mL (86.64 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。 |
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| 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 | 2.0792 mL | 10.3959 mL | 20.7917 mL |
| 5 mM | 0.4158 mL | 2.0792 mL | 4.1583 mL |
| 10 mM | 0.2079 mL | 1.0396 mL | 2.0792 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。
Targeting opioid dysregulation in depression for the development of novel therapeutics
Pharmacol Ther 2019 Sep;201:51-76.PMID:31051197DOI:10.1016/j.pharmthera.2019.04.009.
Since the serendipitous discovery of the first class of modern antidepressants in the 1950's, all pharmacotherapies approved by the Food and Drug Administration for major depressive disorder (MDD) have shared a common mechanism of action, increased monoaminergic neurotransmission. Despite the widespread availability of antidepressants, as many as 50% of depressed patients are resistant to these conventional therapies. The significant length of time required to produce meaningful symptom relief with these medications, 4-6 weeks, indicates that other mechanisms are likely involved in the pathophysiology of depression which may yield more viable targets for drug development. For decades, no viable candidate target with a different mechanism of action to that of conventional therapies proved successful in clinical studies. Now several exciting avenues for drug development are under intense investigation. One of these emerging targets is modulation of endogenous opioid tone. This review will evaluate preclinical and clinical evidence pertaining to opioid dysregulation in depression, focusing on the role of the endogenous ligands endorphin, enkephalin, dynorphin, and nociceptin/orphanin FQ (N/OFQ) and their respective receptors, mu (MOR), delta (DOR), kappa (KOR), and the N/OFQ receptor (NOP) in mediating behaviors relevant to depression and anxiety. Finally, putative opioid based antidepressants that are under investigation in clinical trials, ALKS5461, JNJ-67953964 (formerly LY2456302 and CERC-501) and BTRX-246040 (formerly LY-2940094) will be discussed. This review will illustrate the potential therapeutic value of targeting opioid dysregulation in developing novel therapies for MDD.
"In silico" study of the binding of two novel antagonists to the nociceptin receptor
J Comput Aided Mol Des 2018 Feb;32(2):385-400.PMID:29340866DOI:10.1007/s10822-017-0095-5.
Antagonists of the nociceptin receptor (NOP) are raising interest for their possible clinical use as antidepressant drugs. Recently, the structure of NOP in complex with some piperidine-based antagonists has been revealed by X-ray crystallography. In this study, a multi-flexible docking (MF-docking) procedure, i.e. docking to multiple receptor conformations extracted by preliminary molecular dynamics trajectories, together with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have been carried out to provide the binding mode of two novel NOP antagonists, one of them selective (BTRX-246040, formerly named LY-2940094) and one non selective (AT-076), i.e. able to inactivate NOP as well as the classical µ- k- and δ-opioid receptors (MOP KOP and DOP). According to our results, the pivotal role of residue D1303,32 (upper indexes are Ballesteros-Weinstein notations) is analogous to that enlighten by the already known X-ray structures of opioid receptors: binding of the molecules are predicted to require a slight readjustment of the hydrophobic pocket (residues Y1313,33, M1343,36, I2195,43, Q2806,52 and V2836,55) in the orthosteric site of NOP, accommodating either the pyridine-pyrazole (BTRX-246040) or the isoquinoline (AT-076) moiety of the ligand, in turn allowing the protonated piperidine nitrogen to maximize interaction (salt-bridge) with residue D1303,32 of the NOP, and the aromatic head to be sandwiched in optimal π-stacking between Y1313,33 and M1343,36. The QM/MM optimization after the MF-docking procedure has provided the more likely conformations for the binding to the NOP receptor of BTRX-246040 and AT-076, based on different pharmacophores and exhibiting different selectivity profiles. While the high selectivity for NOP of BTRX-246040 can be explained by interactions with NOP specific residues, the lack of selectivity of AT-076 could be associated to its ability to penetrate into the deep hydrophobic pocket of NOP, while retaining a conformation very similar to the one assumed by the antagonist JDTic into the K-opioid receptor. The proposed binding geometries fit better the binding pocket environment providing clues for experimental studies aimed to design selective or multifunctional opioid drugs.