5-Amino-1MQ (5-amino-1-methylquinolinium) is a small, permanently charged quinolinium compound designed to inhibit nicotinamide N-methyltransferase (NNMT), an enzyme that sits where cellular methyl metabolism meets NAD+ recycling. It came out of a structure-activity program at the University of Texas Medical Branch and was described as a selective, cell-permeable NNMT inhibitor in 2018.
NNMT drew attention after genetic studies in mice linked the enzyme to energy expenditure in fat and liver. A chemical inhibitor offers a way to test those genetic findings with an acute, reversible tool. This article covers the enzyme biology, the compound’s origin, the cell and rodent work published so far, and the gaps that remain.
At a glance
- Class: Small-molecule quinolinium compound; NNMT inhibitor
- Origin: Neelakantan, Watowich and colleagues, University of Texas Medical Branch; selective inhibitors described in 2018
- Structure: Quinoline ring N-methylated at position 1 with an amino group at position 5; C10H11N2+ (cation); MW 159.21 g/mol (cation); CAS 685079-15-6
- Main research areas: NNMT enzymology, SAM and NAD+ metabolism in adipocytes, diet-induced metabolic models in mice
- Regulatory status: Not approved by the FDA; no published human studies; research reagent only
Structure and origin
NNMT methylates nicotinamide and several other pyridine-containing compounds, and for years it was viewed mainly as a clearance enzyme for excess vitamin B3. That view changed when Kraus and colleagues reported that NNMT expression was elevated in white adipose tissue and liver of obese and diabetic mice, and that lowering it changed tissue metabolism (Kraus et al., 2014). A review by Pissios set out the case that NNMT links nicotinamide handling to methylation balance and energy metabolism (Pissios, 2017).
The UTMB group built inhibitors around the product of the reaction. 1-Methylnicotinamide, the methylated product, is itself a weak NNMT inhibitor, and the investigators examined quinolinium analogs that mimic it. Adding substituents around the quinolinium ring changed potency, and the 5-amino variant combined low-micromolar inhibition with cell permeability, despite its fixed positive charge. The small, flat ring is designed to occupy the nicotinamide-binding site of the enzyme (Neelakantan et al., 2018).
Mechanism: what the research shows
NNMT transfers a methyl group from S-adenosylmethionine (SAM) to nicotinamide, producing 1-methylnicotinamide (1-MNA) and S-adenosylhomocysteine. Each turnover consumes SAM, the main methyl donor for histone and DNA methylation, and removes nicotinamide that could otherwise be salvaged back into NAD+. High NNMT activity can therefore act as a sink for both methyl groups and NAD+ precursors (Pissios, 2017).
In the Kraus study, antisense knockdown of NNMT in adipose tissue and liver of mice on a high-fat diet raised tissue SAM and NAD+ levels, increased histone methylation and polyamine flux in adipocytes, and increased energy expenditure in the model (Kraus et al., 2014). Neelakantan and colleagues then showed that 5-amino-1MQ reduced intracellular 1-MNA and raised SAM and NAD+ in cultured adipocytes, indicating target engagement in cells (Neelakantan et al., 2018).
Key areas of study
Enzyme inhibition and selectivity
Biochemical assays have measured inhibition of recombinant NNMT and compared it with related SAM-dependent methyltransferases and enzymes of the NAD+ salvage pathway, such as NAMPT. The reported profile suggested 5-amino-1MQ was selective for NNMT among the enzymes tested (Neelakantan et al., 2018).
Adipocyte biology in cell culture
In differentiating 3T3-L1 adipocytes, the inhibitor reduced lipogenesis alongside the shifts in 1-MNA, SAM and NAD+. These experiments are used to ask whether chemical inhibition reproduces what the genetic knockdown showed in fat tissue (Neelakantan et al., 2018).
Diet-induced metabolic models in mice
In mice with diet-induced obesity, treatment with 5-amino-1MQ was associated with reduced white adipose mass and adipocyte size and lower plasma cholesterol compared with vehicle, without a reported change in food intake (Neelakantan et al., 2018). These readouts are from one mouse study and frame NNMT as a target for further pathway research.
NNMT beyond fat and liver
NNMT is also studied in cancer-associated stroma, liver disease and muscle, where changes in its expression have been linked to methylation and NAD+ metabolism (Pissios, 2017). Small-molecule inhibitors such as 5-amino-1MQ give these fields a pharmacological tool alongside knockdown and knockout models.
What the evidence does not show
The published 5-amino-1MQ literature is small and comes mostly from the group that developed it. Selectivity has been tested against a limited enzyme panel, and full pharmacokinetic and toxicology data have not been published in detail. NNMT biology also differs between tissues and between mice and humans, and some studies suggest its product, 1-MNA, has activity of its own, which complicates simple models. There are no peer-reviewed human studies of 5-amino-1MQ, and mouse adipose readouts do not establish any effect in people.
Regulatory status
5-Amino-1MQ is not approved by the FDA for any use and has not been approved for human use. Rogue Compounds sells it as a research reagent only.
Handling and storage in the lab
Lyophilized 5-Amino-1MQ should be kept sealed and refrigerated at 2–8°C (36–46°F), protected from light. Keep the vial closed between uses to limit exposure to moisture.
Sourcing and documentation
Rogue Compounds has 5-Amino-1MQ made in small batches. Every vial carries a batch number and a QR code that opens the independent U.S. testing lab’s own report for that batch. The same batch COA is posted on the product page and in the COA Library. The compound is also offered as capsules; every capsule batch is tested by an independent U.S. lab and the batch COA is on the product page and in the COA Library.
View 5-AMINO-1MQ on Rogue Compounds
References
- Neelakantan H, et al. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochem Pharmacol. 2018;147:141-152. PMID 29155147
- Kraus D, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014;508(7495):258-262. PMID 24717514
- Pissios P. Nicotinamide N-methyltransferase: more than a vitamin B3 clearance enzyme. Trends Endocrinol Metab. 2017;28(5):340-353. PMID 28291578
Research use only. Rogue Compounds products are sold strictly for laboratory research. They are not for human or veterinary use, and nothing in this article is medical advice. The studies cited here describe published research, not this product or any use of it.