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

LY2940094 is a potent and selective NOP receptor antagonist with no agonist efficacy at concentrations up to 10 µM in CHO cells recombinantly expressing human NOP receptors. [1]

LY2940094 (3, 10, or 30 mg/kg; 2-3 mL/kg; side wall daily; for 4 days) Drinking sites reduce alcohol preference in Indiana (P) and Malkigian Sardinia (msP) in large animals Model: Female alcoholic (P) rat (250-320 g); rat, does not affect food/water recognition or locomotor activity [1]. Male Malchigian Sardinian alcohol-preferring (msP) rats (400-450 g) [1] Dosage: 3, 10, or 30 mg/kg; 2-3 mL/kg Administration: Oral; daily; 4-day results: Reduced home cage ethanol self-administration.

---

In female Indiana Alcohol-Preferring (P) rats with a chronic history of high ethanol consumption, acute oral administration of LY2940094 (30 mg/kg) significantly reduced homecage ethanol (15% v/v) self-administration at both 3 and 12 hours post-treatment. The reduction was maintained over 4 days of subchronic dosing without evidence of tolerance. It did not affect food or water intake or locomotor activity. [1]
In male Marchigian Sardinian Alcohol-Preferring (msP) rats, LY2940094 (30 mg/kg, PO) dose-dependently attenuated continuous ethanol (10% v/v) self-administration at 2, 8, and 24 hours after dosing, without affecting food or water intake. [1]
In female P rats maintained on a progressive ratio operant schedule, oral LY2940094 (30 mg/kg) reduced the motivation to consume ethanol (as indicated by reduced breakpoints) and ethanol-seeking (reduced active lever presses). [1]
In male msP rats, LY2940094 (3 and 30 mg/kg, PO) robustly blocked stress-induced reinstatement to ethanol-seeking elicited by the pharmacological stressor yohimbine (2 mg/kg, IP). [1]
In male Sprague-Dawley rats, LY2940094 (30 mg/kg, PO) completely blocked ethanol (1.1 g/kg, IP)-stimulated dopamine release in the Nucleus Accumbens, without directly affecting dopamine levels when administered alone. [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

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)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)