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    5-Amino-1MQ: What the NNMT Inhibitor Research Shows So Far

    October 20267 min read

    5-Amino-1MQ is a small-molecule NNMT inhibitor, not a peptide. How NNMT links nicotinamide, SAM and NAD+, what the rodent obesity and muscle ageing studies found, and why there are still no human trials.

    Quick Answer

    5-Amino-1MQ (5-amino-1-methylquinolinium) is a small molecule, not a peptide. It inhibits nicotinamide N-methyltransferase (NNMT), an enzyme that uses the methyl donor SAM to methylate nicotinamide, a form of vitamin B3. In mice it reduced fat mass in diet-induced obesity and improved regeneration and strength in aged muscle. Nearly all of this work comes from one research group, its effect on NAD+ is debated, and no human trial has been published.

    5-Amino-1MQ is a quinolinium cation of about 159 daltons, developed to inhibit a single enzyme. The case for studying it rests on what that enzyme does.

    What NNMT does

    NNMT moves a methyl group from S-adenosylmethionine (SAM), the cell's main methyl donor, onto nicotinamide. The products are S-adenosylhomocysteine and 1-methylnicotinamide (1-MNA), which is excreted in urine, partly after further oxidation, so NNMT was long seen as a clearance route for surplus vitamin B3. It is most highly expressed in the liver and is also active in fat tissue (Pissios, 2017).

    This matters for two reasons: nicotinamide feeds the salvage pathway that regenerates NAD+, and every NNMT reaction consumes SAM, the donor that histone and DNA methylation also need.

    In 2014, NNMT was found to be raised in fat and liver of obese and diabetic mice, and knocking it down with antisense oligonucleotides protected mice against diet-induced obesity by increasing energy expenditure. Fat tissue from knockdown animals had more SAM and NAD+ and higher polyamine flux, which the authors linked to the extra energy use (Kraus et al., 2014). In people, NNMT expression in fat tissue is about twice as high in type 2 diabetes and tracks insulin resistance, an observational association rather than proof of cause (Kannt et al., 2015).

    From target to compound

    Stanley Watowich's group at the University of Texas Medical Branch, with chemists at the University of Texas at San Antonio, screened methylated quinoliniums and related scaffolds against NNMT. Quinoliniums inhibited the enzyme at around 1 micromolar, and computer docking placed them in its nicotinamide binding site (Neelakantan et al., 2017). 5-Amino-1MQ was taken forward for its potency and cell permeability. At the concentrations tested it showed little or no activity against three related methyltransferases (COMT, DNMT1 and PRMT3) or against NAMPT and SIRT1, two enzymes of NAD+ metabolism (Neelakantan et al., 2018).

    The rodent obesity studies

    In cultured mouse fat cells, 5-amino-1MQ cut intracellular 1-MNA to about 40% of control, raised SAM and reduced lipid accumulation in maturing fat cells by up to 70%. In male mice made obese on a high-fat diet, 11 days of treatment (nine animals per group) produced a 5.1% loss of body weight against a 1.4% gain in controls, with no change in food intake. Epididymal fat mass fell by about 35%, fat cells were more than 30% smaller and total cholesterol was about 30% lower. No adverse effects were observed, though a study this short cannot establish safety (Neelakantan et al., 2018).

    Two follow-ups from the same group agreed. Combined with a lower-calorie diet, the inhibitor brought body weight, fat mass and liver fat in obese mice down to the levels of lean controls, which the diet alone did not (Sampson et al., 2021). In a 28-day study with eight mice per group, it limited weight and fat gain in a graded way across two treatment levels, improved glucose tolerance and insulin sensitivity, and reduced fatty liver (Babula et al., 2024).

    The muscle ageing studies

    NNMT protein was about three times higher in the leg muscle of old mice than young ones. In 24-month-old male mice with a chemically induced muscle injury, the inhibitor increased muscle stem cell proliferation and fusion, nearly doubled the cross-sectional area of regenerating fibres and raised peak torque by about 70% (Neelakantan et al., 2019).

    A later study treated 22-month-old female mice for eight weeks, with or without progressive weighted wheel running. Against sedentary controls, grip strength rose about 40% with the inhibitor alone, 20% with exercise alone and 60% with both (Dimet-Wiley et al., 2024). Groups held seven to ten animals. See also our overview of myostatin pathway inhibitors.

    How it relates to NAD+ research

    NAD+ declines with age in rodents and humans, and restoring it, usually with precursors such as nicotinamide riboside or NMN, is a major research theme (Covarrubias et al., 2021). The 5-amino-1MQ papers frame NNMT inhibition as a complementary approach: keep nicotinamide in the salvage loop rather than add more.

    The evidence for that link is thinner than the framing suggests. In the 2018 fat-cell work, NAD+ rose about 1.2 to 1.6-fold, but the overall statistical test narrowly missed significance and nicotinamide itself did not change, while SAM rose significantly. A 2017 review noted that NNMT binds nicotinamide weakly (around 430 micromolar) compared with NAMPT, the first salvage enzyme (below 1 micromolar), so it is unlikely to starve NAD+ synthesis, and that NNMT knockdown in mouse liver left NAD+ unchanged. The same review treats 1-MNA as active rather than waste: added to the diet of high-fat-fed mice, it stabilised liver SIRT1 and lowered liver fat and cholesterol (Pissios, 2017). Methyl balance and polyamine flux may matter as much as NAD+, and no study has measured NAD+ in people given 5-amino-1MQ.

    What is not known

    • Human data. No human trial of 5-amino-1MQ has been published, and ClinicalTrials.gov listed no registered study of it in October 2026. Human pharmacokinetics and safety are unknown.
    • Independent replication. Nearly every compound-specific study comes from the Watowich group, and later papers declare that the senior author founded Ridgeline Therapeutics and that co-authors are employees.
    • Study size. Groups of six to twelve mice, mostly male, and no treatment period longer than eight weeks.
    • The target's genetics. Whole-body NNMT knockout mice did not simply resist obesity: effects on weight, insulin sensitivity and glucose tolerance varied by sex and diet (Brachs et al., 2019). Against that, a structurally different inhibitor, JBSNF-000088 from researchers at Sanofi and Jubilant Biosys, reduced body weight and improved insulin sensitivity in obese mice but not in NNMT knockout mice, which supports the target itself (Kannt et al., 2018).

    5-Amino-1MQ is not an approved medicine in the UK, the US or the EU.

    The bottom line

    5-Amino-1MQ is a well-characterised research tool for a plausible metabolic target, selective in enzyme assays and consistent across several rodent studies of obesity and muscle ageing. Those results are early: rodent-only, almost all from one developer-linked group, with the NAD+ story still contested. UK laboratories can find supply details on our 5-Amino-1MQ UK page; it is supplied for laboratory research use only.

    References

    1. Pissios P. 2017. "Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme." Trends in Endocrinology and Metabolism 28(5):340-353. PMID 28291578
    2. Kraus D, et al. 2014. "Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity." Nature 508(7495):258-262. PMID 24717514
    3. Kannt A, et al. 2015. "Association of nicotinamide-N-methyltransferase mRNA expression in human adipose tissue and the plasma concentration of its product, 1-methylnicotinamide, with insulin resistance." Diabetologia 58(4):799-808. PMID 25596852
    4. Neelakantan H, et al. 2017. "Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase." Journal of Medicinal Chemistry 60(12):5015-5028. PMID 28548833
    5. Neelakantan H, et al. 2018. "Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice." Biochemical Pharmacology 147:141-152. PMID 29155147
    6. Sampson CM, et al. 2021. "Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition and enhances metabolic benefits in obese mice." Scientific Reports 11(1):5637. PMID 33707534
    7. Babula JJ, et al. 2024. "Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction." Diabetes, Obesity and Metabolism 26(11):5272-5282. PMID 39161060
    8. Neelakantan H, et al. 2019. "Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle." Biochemical Pharmacology 163:481-492. PMID 30753815
    9. Dimet-Wiley AL, et al. 2024. "Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice." Scientific Reports 14(1):15554. PMID 38969654
    10. Covarrubias AJ, et al. 2021. "NAD+ metabolism and its roles in cellular processes during ageing." Nature Reviews Molecular Cell Biology 22(2):119-141. PMID 33353981
    11. Brachs S, et al. 2019. "Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance." Diabetes 68(3):527-542. PMID 30552109
    12. Kannt A, et al. 2018. "A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders." Scientific Reports 8(1):3660. PMID 29483571

    Frequently asked questions

    Is 5-Amino-1MQ a peptide?

    No. 5-Amino-1MQ (5-amino-1-methylquinolinium) is a small molecule: a methylated quinolinium ion with a molecular weight of about 159 for the cation. It is grouped with research peptides only because it is studied in the same metabolic research areas.

    What does 5-Amino-1MQ inhibit?

    Nicotinamide N-methyltransferase (NNMT), the enzyme that transfers a methyl group from S-adenosylmethionine (SAM) to nicotinamide, producing 1-methylnicotinamide. In enzyme assays it inhibited NNMT at around 1 micromolar and showed little or no activity against three related methyltransferases or the NAD+ enzymes NAMPT and SIRT1.

    Has 5-Amino-1MQ been tested in humans?

    No human trial has been published, and ClinicalTrials.gov listed no registered study of it in October 2026. The evidence consists of cell culture work and studies in obese and aged mice, almost all from a single research group.

    Does 5-Amino-1MQ raise NAD+?

    In cultured mouse fat cells, NAD+ rose by roughly 1.2 to 1.6-fold, although the overall statistical test narrowly missed significance. A 2017 review argued that NNMT is unlikely to control NAD+ levels directly. No human NAD+ data exist.

    Who developed 5-Amino-1MQ?

    Stanley Watowich's group at the University of Texas Medical Branch, working with chemists at the University of Texas at San Antonio, described it in papers from 2017 onwards. Later papers declare that the senior author founded Ridgeline Therapeutics, a company developing NNMT inhibitors.

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