Compound research
5-Amino-1MQ: research overview
5-Amino-1-methylquinolinium (also written 5-AMQ or 5A1MQ) is a small synthetic molecule, not a peptide, belonging to a methylquinolinium series developed as inhibitors of the enzyme nicotinamide N-methyltransferase (NNMT). Compounds of this series have been studied in enzyme and cell assays and in rodent models of diet-induced obesity, in work examining the role of NNMT in nicotinamide, NAD+ and methyl-group metabolism.1–3, 5, 6
Mechanism at a glance
- Nicotinamide N-methyltransferase (NNMT)NNMT is the cytosolic enzyme that transfers a methyl group from SAM to nicotinamide; in the structure-activity work, docking placed these quinolinium analogues in the nicotinamide (substrate) site and docking scores tracked measured inhibitory potency.2, 3
- NAD+ salvage pathwayNNMT consumes nicotinamide, which is otherwise recycled to NAD+; intracellular NAD+ was measured in cultured adipocytes exposed to inhibitors of this series, and NNMT knockdown in mice was linked to NAD+ and sirtuin signalling.1, 3
- S-adenosylmethionine (SAM) methyl-donor poolNNMT uses SAM as the methyl donor, so inhibition has been studied as a way to alter cellular SAM availability and downstream methylation.1, 3
- Adipocyte lipid metabolismLipogenesis and the NNMT reaction product 1-methylnicotinamide were measured in cultured adipocytes exposed to inhibitors of this series.3
These pathways are linked, because NNMT consumes both nicotinamide and the methyl donor SAM, and how far the biochemical changes reported in cultured cells and rodent tissue apply to humans is still being investigated.1, 3, 6
What it is
5-Amino-1MQ is a small organic molecule of the methylquinolinium class, carrying a permanent positive charge on the quinolinium nitrogen and, as its name indicates, a primary amine at the 5-position. It is not a peptide and contains no amino-acid chain. Its scaffold comes from a structure-activity study of N-methylated quinolinium, isoquinolinium, pyridinium and benzimidazolium analogues, in which the quinoliniums were taken forward as the more active series against NNMT; methylquinoliniums carrying a primary amine were then characterised further.2, 3, 5
Naming
The compound appears in the literature as 5-amino-1-methyl quinolinium, abbreviated 5-AMQ, and as 5A1MQ. Other papers from the same programme use the generic abbreviation NNMTi for small-molecule NNMT inhibitors rather than a compound name.4–6
How it acts
NNMT catalyses N-methylation of nicotinamide using SAM as the methyl donor, producing 1-methylnicotinamide. In the structure-activity work, computational docking placed the quinolinium analogues in the substrate-binding site of the enzyme. In cultured adipocytes, intracellular 1-methylnicotinamide, NAD+, SAM and lipogenesis have been used as readouts of NNMT inhibition. Membrane permeability was characterised in artificial-membrane and Caco-2 cell assays, and selectivity was tested against structurally related SAM-dependent methyltransferases and against enzymes of the NAD+ salvage pathway.2, 3
Why the target was chosen
Interest in NNMT as a metabolic target followed work in which Nnmt was knocked down in white adipose tissue and liver of mice, linking the enzyme to NAD+, SAM, histone methylation and polyamine metabolism. That study used gene knockdown rather than this molecule.1
Research status
The published work on 5-amino-1MQ and its series is preclinical. It covers enzyme and cell assays; rodent models of diet-induced obesity in which body composition, glucose and insulin measures, liver histopathology and tissue distribution were examined; a study in aged mice of a compound from the same series, reported only as an NNMT inhibitor, which examined muscle stem-cell activity and regeneration after an induced muscle injury; and analytical and pharmacokinetic characterisation in rats. In the 2024 mouse study the authors declare that some of them founded, are employed by or formerly worked for a company developing NNMT inhibitors, while the 2018 and 2019 papers declare no competing interests.2–6
Published research at a glance
- In vitro
Structure-activity relationships of N-methylated quinolinium and related scaffolds at NNMT, with docking to the substrate-binding site
- In vitro
Membrane permeability, selectivity against related methyltransferases and NAD+ salvage enzymes, and 1-methylnicotinamide, NAD+, SAM and lipogenesis readouts in cultured adipocytes
- Animal model
Body weight, white adipose tissue mass, adipocyte size and plasma lipid measures in diet-induced obese mice
- Animal model
Muscle stem-cell activity, myofibre cross-sectional area and contractile function after an induced muscle injury in aged mice, using an inhibitor of the same series reported only as NNMTi
- Animal model
A validated LC-MS/MS assay for 5-amino-1-methyl quinolinium in rat plasma and urine, applied to pharmacokinetic characterisation in rats
- Animal model
Body composition, blood glucose and insulin measures, liver histopathology, plasma pharmacokinetics and tissue distribution in diet-induced obese mice
Research status: The references listed here describe cell and rodent studies only and report no human clinical trials of 5-amino-1MQ.3–6
References
- Kraus D, Yang Q, Kong D, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature (2014). doi:10.1038/nature13198
- Neelakantan H, Wang HY, Vance V, Hommel JD, McHardy SF, Watowich SJ. Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. Journal of Medicinal Chemistry (2017). doi:10.1021/acs.jmedchem.7b00389
- Neelakantan H, Vance V, Wetzel MD, Wang HL, McHardy SF, Finnerty CC, Hommel JD, Watowich SJ. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochemical Pharmacology (2018). doi:10.1016/j.bcp.2017.11.007
- Neelakantan H, Brightwell CR, Graber TG, Maroto R, Wang HL, McHardy SF, Papaconstantinou J, Fry CS, Watowich SJ. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochemical Pharmacology (2019). doi:10.1016/j.bcp.2019.02.008
- Awosemo O, Neelakantan H, Watowich S, Ma J, Wu L, Chow DS, Liang D. Development & validation of LC-MS/MS assay for 5-amino-1-methyl quinolinium in rat plasma: Application to pharmacokinetic and oral bioavailability studies. Journal of Pharmaceutical and Biomedical Analysis (2021). doi:10.1016/j.jpba.2021.114255
- Babula JJ, Bui D, Stevenson HL, Watowich SJ, Neelakantan H. Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction. Diabetes, Obesity & Metabolism (2024). doi:10.1111/dom.15879
Literature summary compiled on 15 October 2026.