5-Amino-1MQ
Also known as: 5-Amino-1-methylquinolinium, 5-AMQ, 5A1MQ, 5-Amino-1-methylquinolinium iodide
Evidence: Preclinical
Overview
Small-molecule NNMT inhibitor (5-amino-1-methylquinolinium), not a peptide; in diet-induced obese mice it lowered body weight and fat mass and raised adipocyte NAD+ without changing food intake.
5-Amino-1MQ is a membrane-permeable methylquinolinium inhibitor of nicotinamide N-methyltransferase (NNMT) from the Watowich lab at UTMB (Neelakantan 2017). NNMT knockdown protected mice from diet-induced obesity (Kraus 2014). In diet-induced obese mice, 5-amino-1MQ given subcutaneously for 11 days lowered body weight, white fat mass and cholesterol without changing food intake (Neelakantan 2018); 28 days of daily dosing limited fat gain, improved insulin sensitivity and reduced fatty liver (Babula 2024). Combined with a lean diet it normalised body composition (Sampson 2021). In aged mice it improved muscle stem cell function and grip strength (Neelakantan 2019; Dimet-Wiley 2024). Rat PK shows oral activity. No human study is published or registered.
Benefits
Reduced body weight, white fat mass and plasma cholesterol (diet-induced obese mice), improved glucose tolerance and less liver fat (obese mice), raised NAD+ in adipocytes (in vitro), stronger grip and muscle regeneration in aged mice
Dosing reference
- Research dose
- 50 to 100 mg daily by mouth (vendor/community range, no published human dose; mouse studies used about 34 mg/kg/day subcutaneously)
- Range
- 50000 to 100000 mcg, 1x daily
Oral capsule in community use. Published dosing is rodent: 20 mg/kg subcutaneously three times daily for 11 days in obese mice (Neelakantan 2018), once-daily dosing for 28 days (Babula 2024), and single IV or oral doses in rats for PK (Awosemo 2021). No human dose has been studied.
Mechanism
5-Amino-1MQ inhibits NNMT, the cytosolic enzyme that methylates nicotinamide to 1-methylnicotinamide (1-MNA) using S-adenosylmethionine (SAM). In cultured adipocytes it lowered 1-MNA, raised intracellular NAD+ and SAM, and suppressed lipogenesis, without inhibiting related methyltransferases or NAD+ salvage enzymes (Neelakantan 2018). NNMT is highly expressed in white fat of obese mice, and its knockdown raised energy expenditure through increased SAM and NAD+ flux (Kraus 2014). Downstream effects on SIRT1 and fat browning are proposed rather than shown for this compound.
Evidence
Preclinical: animal or in vitro data only
- NNMT knockdown in fat and liver protected mice against diet-induced obesity and raised energy expenditure (Kraus et al., 2014)
- 20 mg/kg three times daily subcutaneously for 11 days lowered body weight, white fat mass, adipocyte size and cholesterol in diet-induced obese mice, with no change in food intake (Neelakantan et al., 2018)
- Once-daily dosing for 28 days dose-dependently limited weight and fat gain, improved glucose tolerance and reduced hepatic steatosis in obese mice (Babula et al., 2024)
- Raised grip strength about 40% in aged sedentary mice and added to exercise effects (Dimet-Wiley et al., 2024)
- Human-trial status: no human study published or registered on ClinicalTrials.gov
References
- Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Kraus D, Yang Q, Kong D, et al., Nature, 2014
- 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
- Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition and enhances metabolic benefits in obese mice. Sampson CM, Dimet AL, Neelakantan H, et al., Scientific Reports, 2021
- 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
- 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
Side effects
No published human safety or pharmacokinetic data exists; oral use is entirely community-derived. Anecdotal reports mention insomnia, appetite loss, and mild GI upset. The effects of chronic NNMT inhibition in humans are unknown.
Storage
- Storage
- Room temperature, dry (general small-molecule guidance; no compound-specific CoA located)
- Lyophilized
- 12+ months
Pharmacology
- Half-life
- 3.8 h IV and 6.9 h oral (rat); no human PK data (Awosemo 2021)
- Bioavailability
- Oral 38.4% (rat); no human data (Awosemo 2021)
- Molecular weight
- 159.21 Da