Additional Research Compound · For laboratory research use only
Also known as 5-Amino-1-methylquinolinium, NNMTi
5-Amino-1MQ (5-amino-1-methylquinolinium, also abbreviated 5-AMQ or 5A1MQ) is a small-molecule quinolinium cation that inhibits nicotinamide N-methyltransferase (NNMT), the cytosolic enzyme that methylates nicotinamide using S-adenosylmethionine (SAM). It emerged from a structure-activity study of N-methylated quinolinium, isoquinolinium, pyridinium and benzimidazolium analogues at the University of Texas Medical Branch1.
Published research is preclinical and comes largely from one group, several of whose authors have declared employment with or interests in Ridgeline Therapeutics5,6,7. Studies have examined enzyme inhibition and selectivity, membrane permeability, cultured adipocytes and myoblasts, diet-induced obese mice, aged mouse muscle and rat pharmacokinetics1,2,3,4,6.
As described in the research literature
As described in the research literature, quinoliniums were identified as a scaffold with low micromolar NNMT inhibition, and docking placed the inhibitors in the nicotinamide substrate-binding site of the enzyme1. Methylquinolinium analogues with primary amine substitutions showed high permeability in parallel artificial membrane and Caco-2 assays, and did not inhibit related SAM-dependent methyltransferases or NAD+ salvage pathway enzymes2.
In cultured adipocytes, the inhibitors reduced the NNMT product 1-methylnicotinamide, increased intracellular NAD+ and SAM, and suppressed lipogenesis2. The authors proposed that increased flux of NAD+ and SAM underlies the effects seen in their mouse models, and in C2C12 myoblasts NNMT inhibition was accompanied by changes in NAD+/NADH redox state during differentiation2,3.
What published studies have examined
Structure-activity work screened a series of N-methylated aromatic cations against NNMT and correlated docking scores with measured IC50 values1. Follow-up work characterised permeability and selectivity against structurally related methyltransferases and NAD+ salvage enzymes2.
Body weight, white adipose mass, adipocyte size, plasma cholesterol and food intake were measured in diet-induced obese mice2. A 2024 study examined body composition, glucose tolerance, insulin sensitivity, liver histopathology and circulating liver markers, alongside tissue distribution6. Combining NNMT inhibition with a switch to a low-fat diet was used to examine the caecal microbiome5.
In 24-month-old mice with an acute barium chloride injury to the tibialis anterior, a small-molecule NNMT inhibitor developed by the same group was studied for muscle stem cell proliferation and fusion, myofibre cross-sectional area and contractile torque3. A later study in aged mice compared NNMT inhibition, intensive exercise and their combination on grip strength, running capacity, muscle fibre characteristics, intramyocellular lipid and muscle proteome and metabolome7.
A liquid chromatography-tandem mass spectrometry method for 5-amino-1-methylquinolinium in rat plasma and urine was developed and validated, and applied to a rat pharmacokinetic study4. Plasma and tissue pharmacokinetics in mice were characterised in the 2024 study6.
Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase.
Neelakantan H, Wang HY, Vance V, et al. Journal of Medicinal Chemistry, 2017.
Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice.
Neelakantan H, Vance V, Wetzel MD, et al. Biochemical Pharmacology, 2018.
Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle.
Neelakantan H, Brightwell CR, Graber TG, et al. Biochemical Pharmacology, 2019.
Development & validation of LC-MS/MS assay for 5-amino-1-methyl quinolinium in rat plasma: Application to pharmacokinetic and oral bioavailability studies.
Awosemo O, Neelakantan H, Watowich S, et al. Journal of Pharmaceutical and Biomedical Analysis, 2021.
Reduced calorie diet combined with NNMT inhibition establishes a distinct microbiome in DIO mice.
Dimet-Wiley A, Wu Q, Wiley JT, et al. Scientific Reports, 2022.
Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction.
Babula JJ, Bui D, Stevenson HL, et al. Diabetes, Obesity & Metabolism, 2024.
Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice.
Dimet-Wiley AL, Latham CM, Brightwell CR, et al. Scientific Reports, 2024.
This page is provided for research and educational reference only. It does not constitute medical advice, dosing guidance, or a recommendation for use. All compounds are strictly for laboratory and in-vitro research purposes.