Varenicline-15N,13C,d2 is 15N and deuterium labeled Varenicline. Varenicline (CP 526555) is an orally active partial agonist (IC50=250 nM) of the α4β2 nicotinic acetylcholine receptor (α4β2 nAChR), the primary mediator of nicotine dependence. Varenicline is also a partial agonist of α6β2 nAChR and a full agonist of α6β2 nAChR. Varenicline blocks the direct agonist effect of nicotine on nAChR while stimulating nAChR at a more moderate level, and is widely used as an aid to smoking cessation.

Physicochemical Properties

Molecular Formula	C1213CH11D2N215N
Molecular Weight	215.26
Appearance	Typically exists as solid at room temperature
Synonyms	Varenicline-15N,13C,d2; CP 526555-15N,13C,d2
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	Stable heavy isotopes of hydrogen, carbon, and other elements have been incorporated into drug molecules, primarily as quantitative tracers during drug development. Studies involving the use of deuterium-labeled drugs in humans have shown that these compounds may have certain advantages over their non-deuterated counterparts. Deuterated drugs have attracted attention due to their potential to affect the pharmacokinetic and metabolic characteristics of drugs. Deuttetrabenazine is the first deuterated drug approved by the US Food and Drug Administration. Deuttetrabenazine is indicated for the treatment of chorea associated with Huntington's disease and tardive dyskinesia. Ongoing clinical trials indicate that many other deuterated compounds are being evaluated for use as therapeutics in humans, rather than just as research tools. [1] Varenicline (200 μM, 24 h) had no significant effect on HUVEC cell viability [4]. Varenicline (100 μM, 30 min) significantly activated the ERK1/2 and p38 signaling pathways in HUVEC cells, and thus Varenicline (100 μM, 24 h) reduced the expression of VE-cadherin in HUVEC cells[4]. Varenicline (100 μM, 4 h) promoted the cell migration of HUVEC cells by 2.4 times[4].
ln Vivo	Varenicline (0.5, 1 mg/kg, subcutaneous injection, immediate administration) dose-dependently reverses fentanyl-induced respiratory depression in rats while mildly alleviating the sedative effects of fentanyl [5]. Varenicline (0.004–0.04 mg/kg/h, intravenous infusion, 23 hours a day, 7-10 days) dose-dependently reduces nicotine (0.0032 mg/kg/inj) in adult rhesus monkeys experienced with cocaine and nicotine use self-administered levels alone and in combination with cocaine (0.0032 mg/kg/inj) without significant effects on food-maintained responses [6]. Varenicline (0.178-5.6 mg/kg, oral, immediate administration) showed antidepressant-like activity in the forced swim test in C57BL/6J and CD-1 mice [7].
References	[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019 Feb;53(2):211-216. [2]. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA. 2014 Jul;312(2):155-61. [3]. Ultrapotent chemogenetics for research and potential clinical applications. Science. 2019;364(6436):eaav5282. [4]. Varenicline promotes endothelial cell migration by lowering vascular endothelial-cadherin levels via the activated α7 nicotinic acetylcholine receptor-mitogen activated protein kinase axis. Toxicology. 2017;390:1-9. [5]. Countering Opioid-induced Respiratory Depression in Male Rats with Nicotinic Acetylcholine Receptor Partial Agonists Varenicline and ABT 594. Anesthesiology. 2020 May;132(5):1197-1211. [6]. Effects of chronic varenicline treatment on nicotine, cocaine, and concurrent nicotine+cocaine self-administration. Neuropsychopharmacology. 2014 Apr;39(5):1222-31. [7]. Varenicline has antidepressant-like activity in the forced swim test and augments sertraline's effect. Eur J Pharmacol. 2009 Mar 1;605(1-3):114-6.

Solubility Data

Solubility (In Vitro)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	4.6455 mL	23.2277 mL	46.4554 mL
	5 mM	0.9291 mL	4.6455 mL	9.2911 mL
	10 mM	0.4646 mL	2.3228 mL	4.6455 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.