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| Targets |
Nicotinamide N-methyltransferase (NNMT). NNMTi selectively binds to the NNMT substrate-binding site residues. It is designed to inhibit NNMT without affecting related methyltransferases or enzymes in the NAD+ salvage pathway, such as nicotinamide phosphoribosyltransferase (NAMPT), ensuring its specificity for the target enzyme. By blocking NNMT activity, the compound prevents the conversion of nicotinamide to 1-MNA, thereby influencing cellular NAD+ levels and downstream metabolic and signaling pathways that are dependent on this critical cofactor.
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| ln Vitro |
In C2C12 myoblast differentiation, NNMTi (10-30 μM; 96 hours) causes a concentration-related increase in myoblast differentiation. Compared to untreated developed myoblasts (which produced 12% MHC-positive myotube nuclei), 30 μM NNMTi resulted in a 45% increase in myoblast differentiation, producing 18% MHC-positive myotube nuclei [1].
NNMTi demonstrates potent in vitro activity by directly inhibiting purified NNMT enzyme with an IC50 of 1.2 μM under assay conditions using 50 μM SAM and 100 μM nicotinamide as substrates. In cellular models, it effectively reduces 3T3-L1 adipocyte lipogenesis with an EC50 of 30 μM and lowers intracellular 1-methylnicotinamide levels with an EC50 of 2.3 μM, confirming target engagement in living cells. Furthermore, NNMTi promotes myoblast differentiation in C2C12 cells, a mouse myoblast cell line, demonstrating its ability to modulate cellular differentiation programs. These in vitro activities collectively establish NNMTi as a robust chemical probe for studying NNMT function in various cell types. |
| ln Vivo |
NNMTi (subcutaneous injection; 5 mg/kg and 10 mg/kg; 2 weeks, 1 week prior to and 1 week following injury) increases the proliferation of muscle cells during the process of recovering from injury. The percentage of active muSCs was 60% and 75%, respectively. Under NNMTi therapy, the proportion of fibers containing EdU+ myonuclei rose by 40% and 48% at 5 mg/kg and 10 mg/kg, respectively. Control fused myonuclei had odds ratios of 0.58 and 0.53 times, respectively, the NNMTi low and high doses [2]. Mice administered with NNMTi (subcutaneous injection; 10 mg/kg; 1 week) did not exhibit systemic toxicity, and there was no difference in glucose, cholesterol, plasma protein, or electrolyte levels between the control and NNMTi-treated groups. In aged rats, repeated daily injection of NNMTi for one week following injury did not result in any negative behavioral effects or systemic toxicity [2].
In vivo, NNMTi treatment has been shown to rescue age-related deficits in muscle stem cell (muSC) activity and promote superior muscle regeneration following injury in aged mice. In a study using 24-month-old mice subjected to acute muscle injury via barium chloride injection, administration of NNMTi at low (5 mg/kg) and high (10 mg/kg) doses for one week post-injury significantly enhanced muSC proliferation and fusion. This led to nearly a 2-fold greater myofiber cross-sectional area (CSA) and a shift in fiber size distribution towards larger myofibers compared to controls, indicating improved muscle recovery. Prolonged NNMTi treatment for three weeks post-injury further supported these regenerative effects, highlighting its potential for treating age-related muscle decline. |
| Enzyme Assay |
The in vitro enzyme inhibition assay for NNMTi is performed by incubating purified recombinant NNMT enzyme with varying concentrations of the inhibitor in the presence of its substrates, SAM and nicotinamide. The reaction is typically carried out in a suitable buffer at physiological pH and temperature. The production of 1-methylnicotinamide is then quantified using a fluorometric or mass spectrometry-based method to determine the residual enzyme activity. The IC50 value, representing the concentration of NNMTi required to inhibit 50% of the enzyme's activity, is calculated by plotting the percentage of inhibition against the log of inhibitor concentration.
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| Cell Assay |
For cellular activity assessment, 3T3-L1 preadipocytes are differentiated into mature adipocytes and treated with various concentrations of NNMTi. Lipogenesis is quantified by measuring lipid accumulation using Oil Red O staining or by assessing the incorporation of radiolabeled acetate into lipids. The intracellular level of 1-methylnicotinamide, the direct product of NNMT activity, is measured by LC-MS/MS to confirm on-target inhibition. Additionally, C2C12 myoblasts are treated with NNMTi, and myoblast differentiation is assessed by analyzing the expression of myogenic markers such as myosin heavy chain (MHC) via immunocytochemistry or Western blot.
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| Animal Protocol |
In vivo activity of NNMTi is evaluated in aged (24-month-old) mouse models of acute muscle injury. Muscle injury is induced by injecting barium chloride into the tibialis anterior (TA) muscle. NNMTi is administered daily via intraperitoneal injection at doses of 5 mg/kg or 10 mg/kg for one to three weeks post-injury. Muscle stem cell activity is analyzed by administering 5-ethynyl-2'-deoxyuridine (EdU) systemically to label proliferating cells, followed by immunofluorescence staining of muscle sections to detect EdU incorporation and myogenic markers. Muscle regeneration is quantified by measuring myofiber cross-sectional area (CSA) and analyzing fiber size distribution from histologically stained muscle sections.
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| ADME/Pharmacokinetics |
NNMTi has a molecular weight of 286.11 g/mol and a chemical formula of C10H11IN2. It is soluble in DMSO at concentrations up to 57 mg/mL (199.22 mM) and in water up to 5-7 mg/mL. For in vivo studies, it can be formulated as a homogeneous suspension in CMC-Na at a concentration of ≥5 mg/mL for oral administration. Alternatively, a clear solution can be prepared using 5% DMSO, 40% PEG300, 5% Tween 80, and 50% ddH2O, achieving a solubility of 2.85 mg/mL (9.96 mM). The compound should be stored as a solid at -20°C for long-term stability.
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| Toxicity/Toxicokinetics |
Based on available safety data, NNMTi is classified as a research chemical and should be handled with standard laboratory precautions. It is not intended for human or veterinary use. Specific toxicological data, such as LD50 values, are not typically detailed in standard product documentation, as it is used exclusively for in vitro and preclinical in vivo research. However, as with all chemical reagents, appropriate personal protective equipment (PPE) should be worn, and the compound should be handled in a well-ventilated area to minimize exposure.
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| References |
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| Additional Infomation |
NNMTi is a research-grade compound exclusively used for laboratory investigations into NNMT biology. It is not approved for clinical use and is not intended for therapeutic applications. The compound has been cited in high-impact journals, including Nature Medicine, for its role in activating senescent muscle stem cells and improving the regenerative capacity of aged skeletal muscle. Its development has provided critical pharmacological validation of NNMT as a target for addressing age-related muscle decline and metabolic disorders. NNMTi is available as a high-purity chemical reagent (>97-99%) from various commercial suppliers for research purposes.
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| Molecular Formula |
C10H11IN2
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| Molecular Weight |
286.1122
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| Exact Mass |
285.996
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| CAS # |
42464-96-0
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| PubChem CID |
66522933
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| Appearance |
Brown to reddish brown solid powder
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
13
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| Complexity |
158
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| Defined Atom Stereocenter Count |
0
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| SMILES |
[I-].[N+]1(C)=CC=CC2=C(C=CC=C12)N
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| InChi Key |
JPEZFBFIRRAFNR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C10H10N2.HI/c1-12-7-3-4-8-9(11)5-2-6-10(8)12;/h2-7,11H,1H3;1H
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| Chemical Name |
1-methylquinolin-1-ium-5-amine;iodide
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: 20.83 mg/mL (72.80 mM)
H2O: 2.27 mg/mL (7.93 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (7.27 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 (7.27 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4952 mL | 17.4758 mL | 34.9516 mL | |
| 5 mM | 0.6990 mL | 3.4952 mL | 6.9903 mL | |
| 10 mM | 0.3495 mL | 1.7476 mL | 3.4952 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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