NOP Receptor/ORL1
Nociceptin/orphanin FQ (NOP) receptor antagonist (Ki = 0.105 nM, Kb = 0.166 nM) [1]

LY2940094 是一种强效、选择性的NOP受体拮抗剂，在表达人源NOP受体的CHO细胞中，浓度高达10 µM时未显示激动剂活性。 [1]

LY2940094 (3、10 或 30 mg/kg；2-3 mL/kg；每天侧壁；持续 4 天) 饮酒地减少 印第安纳州酒精偏好 (P) 和马尔基吉安撒丁岛酒精偏好 (msP) 大动物模型：雌性嗜酒（P）大鼠（250-320 g）；鼠，不影响食物/水的认可或运动活动[1]。雄性马尔基吉亚撒丁岛酒精偏好 (msP) 大鼠 (400-450 g)[1] 剂量：3、10 或 30 mg/kg； 2-3 mL/kg 给药方式：口服；日常的; 4 天 结果：减少了家笼乙醇的自我施用。

---

在具有长期高乙醇摄入史的雌性印第安纳嗜酒 (P) 大鼠中，急性口服给药 LY2940094 (30 mg/kg) 在给药后3小时和12小时均显著减少了家庭笼内乙醇 (15% v/v) 的自我给药行为。该效应在亚慢性给药（连续4天）期间得以维持，未出现耐受现象。它不影响食物或水的摄入，也不影响自发活动。 [1]
在雄性马基希安-撒丁岛嗜酒 (msP) 大鼠中，口服 LY2940094 (30 mg/kg) 剂量依赖性地减少了给药后2、8和24小时的持续性乙醇 (10% v/v) 自我给药，且不影响食物或水摄入。 [1]
在按渐进比率操作程序训练的雌性P大鼠中，口服 LY2940094 (30 mg/kg) 降低了对乙醇的动机（表现为断点降低）和乙醇寻求行为（主动压杆次数减少）。 [1]
在雄性msP大鼠中，口服 LY2940094 (3 和 30 mg/kg) 显著阻断了由药理应激源育亨宾 (2 mg/kg, IP) 诱发的应激诱导的乙醇寻求行为复吸。 [1]
在雄性Sprague-Dawley大鼠中，口服 LY2940094 (30 mg/kg) 完全阻断了乙醇 (1.1 g/kg, IP) 刺激的伏隔核内多巴胺释放，而单独给药时不影响多巴胺水平。 [1]

Female Alcohol-Preferring (P) rats (250-320 g); Male Marchigian Sardinian Alcohol-Preferring (msP) rats (400-450 g)
3, 10, or 30 mg/kg; 2-3 mL/kg
Administered orally; daily; 4 days

---

Homecage Ethanol Self-Administration in P rats: Female Indiana Alcohol-Preferring (P) rats were individually housed with ad libitum access to chow, water, and 15% (v/v) ethanol. LY2940094 was dissolved in 20% Captisol in 25 mM phosphate buffer (pH 3) and administered orally (PO) in a volume of 2-3 ml/kg, 5 minutes before the onset of the dark phase. Ethanol, water, and food consumption were monitored for 12 hours using a force transduction system. Locomotor activity was monitored via infrared sensors. Acute dosing used a within-subjects, counterbalanced Latin-square design with 3-4 days washout between doses. Subchronic dosing involved 4 daily administrations in a between-subjects design. [1]
Homecage Ethanol Self-Administration in msP rats: Male Marchigian Sardinian Alcohol-Preferring (msP) rats were individually housed with ad libitum access to chow, water, and 10% (v/v) ethanol. LY2940094 (vehicle, 3, 30 mg/kg, PO) was administered 60 minutes before the dark cycle in a within-subjects, counterbalanced design. Ethanol and water intake volumes were measured at 2, 8, and 24 hours post-dose using graduated cylinders. Food intake was measured by weighing the food basket. [1]
Progressive Ratio Operant Responding for Ethanol in P rats: Female P rats were trained to self-administer 15% ethanol (v/v) in operant chambers under an arithmetic progressive ratio schedule. After achieving stable performance, rats received oral doses of vehicle, LY2940094 (3, 10, 30 mg/kg), or naltrexone (10 mg/kg) 60 minutes prior to a 30-minute operant session, using a within-subject counterbalanced Latin-square design with 3-4 days washout. Breakpoints (highest fixed-ratio completed) and active/inactive lever presses were recorded. [1]
Stress-Induced Reinstatement to Ethanol-Seeking in msP rats: Male msP rats were trained to self-administer 10% ethanol (v/v) under a fixed-ratio-1 schedule in operant chambers. After extinction of lever pressing, rats were pretreated with LY2940094 (0, 3, 10 mg/kg, PO) 60 minutes before a reinstatement test. Thirty minutes before the test (i.e., 30 minutes after LY2940094), rats received the stressor yohimbine (2 mg/kg, IP). The session was conducted under extinction conditions, and responses on the previously active lever were recorded. [1]
In vivo Microdialysis in Sprague-Dawley rats: Male Sprague-Dawley rats with guide cannulae implanted in the Nucleus Accumbens were used. A 5 µM concentration of nomifensine was perfused via reverse microdialysis to facilitate dopamine detection. Rats received vehicle or LY2940094 (30 mg/kg, PO) prior to a vehicle or ethanol (1.1 g/kg, IP, as 15% v/v in saline) challenge. Dialysate samples were collected to measure extracellular dopamine levels. [1]

Following oral administration of LY2940094 at a dose of 10 mg/kg, the occupancy of NOP receptors in the brain reached 62%. [1] Pharmacokinetic characteristics indicated that the therapeutic effect lasted for 12 hours after oral administration. [1]

In animal studies, LY2940094 was well tolerated. At doses that reduced ethanol intake (up to 30 mg/kg, orally), it did not affect food or water intake, body weight, or general muscular activity in P or msP rats. [1] In P rats, no significant tolerance to the effect of reducing ethanol intake was observed after 4 days of subchronic administration (30 mg/kg/day). [1]

[1]. 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.

BTRX-246040 is currently undergoing clinical trial NCT03193398 (BTRX-246040 administered once daily for the treatment of patients with major depressive disorder). LY2940094 is a novel, orally bioavailable, small-molecule NOP receptor antagonist. Its chemical name is [2-[4-[(2-chloro-4,4-difluorospiro[5H-thieno[2,3-c]pyran-7,4'-piperidin]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-pyridyl]methanol. [1] This study provides the first in vivo evidence that NOP receptor blockade can attenuate self-administration of ethanol, motivation for ethanol, stress-induced relapse of ethanol craving, and ethanol-stimulated mesolimbic dopamine release. [1]
This article discusses the seemingly contradictory finding that both NOP agonists and antagonists, LY2940094, can reduce alcohol-related behaviors. The hypothesis is that long-term use of agonists may lead to receptor desensitization/internalization, resulting in a functional blockade similar to that of antagonists. [1]
Preclinical data suggest that LY2940094 may have the potential to treat alcohol use disorder. [1]

C22H23CLF2N4O2S

480.958429574966

480.12

C, 54.94; H, 4.82; Cl, 7.37; F, 7.90; N, 11.65; O, 6.65; S, 6.67

1307245-86-8

LY2940094 tartrate; 1307245-87-9

52914971

White to yellow solid powder

3.1

91.6

1

8

4

32

672

0

NKQHBJNRBKHUQR-UHFFFAOYSA-N

InChI=1S/C22H23ClF2N4O2S/c1-14-16(11-29(27-14)20-15(12-30)3-2-6-26-20)10-28-7-4-21(5-8-28)19-17(9-18(23)32-19)22(24,25)13-31-21/h2-3,6,9,11,30H,4-5,7-8,10,12-13H2,1H3

[2-[4-[(2-chloro-4,4-difluorospiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridin-3-yl]methanol

BTRX 246040; BTRX246040; BTRX-246040; LY-2940094; LY 2940094; LY2940094

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~41.7 mg/mL (~86.6 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.32 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.08 mg/mL (4.32 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

---

View More

配方 3 中的溶解度: ≥ 2.08 mg/mL (4.32 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 悬浮液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。