Key findings
- Screening of N-methylated quinolinium, isoquinolinium, pyridinium and benzimidazolium analogues identified quinoliniums as the scaffold reaching low micromolar inhibition of the enzyme, with docking scores correlating with the measured IC50 values. [1]
- Methylquinolinium analogues with primary amine substitutions crossed membranes in both passive and active permeability assays and did not inhibit related methyltransferases or enzymes of the NAD+ salvage pathway. [2]
- In cultured adipocytes the inhibitors lowered intracellular 1-methylnicotinamide, raised intracellular NAD+ and S-adenosylmethionine, and suppressed lipogenesis. [2]
- In cultured C2C12 myoblasts the inhibitor promoted differentiation with accompanying changes in the cellular NAD+ and NADH redox state. [3]
Identity and structure
- Scaffold
- A quinolinium bearing an N-methyl group, from the series in which primary amine substitutions gave the highest membrane permeability [1][2]
- Enzyme target
- Nicotinamide N-methyltransferase, a cytosolic enzyme that transfers a methyl group from S-adenosylmethionine to nicotinamide to form 1-methylnicotinamide [1][4]
- Binding site
- Docking placed the quinolinium analogues at the substrate binding site of the enzyme, the site that binds nicotinamide, rather than at the cofactor site [1]
- Form as supplied
- Solid; the counterion is not stated in the cited work
Mechanism as studied
The structure-activity work presents the molecule as a substrate-site binder. Screening across four N-methylated heterocyclic scaffolds spanned more than a thousand-fold in activity and singled out quinoliniums, and computational docking to the nicotinamide binding site correlated with the measured IC50 values, which the authors read as selective binding to substrate-site residues. [1]
The permeability and selectivity work adds the second half of the argument: a primary amine substitution gave high permeability across membranes by both passive and active transport, while the analogues did not inhibit structurally related S-adenosylmethionine-dependent methyltransferases or NAD+ salvage pathway enzymes. In adipocytes the consequence was a lower level of the enzyme's reaction product and higher levels of NAD+ and S-adenosylmethionine, which the authors propose as the flux change underlying the cellular observations. [2]
Muscle work connects the same enzyme to the NAD+ salvage pathway and sirtuin 1 activity, reporting that the enzyme is overexpressed in aged skeletal muscle and that inhibitor treatment raised muscle stem cell proliferation and fusion, with parallel differentiation changes in cultured myoblasts. [3]
Research findings
In vitro
- System
- Enzyme inhibition screening of N-methylated quinolinium, isoquinolinium, pyridinium and benzimidazolium or benzothiazolium analogues, with computational docking
- Measured
- IC50 for nicotinamide N-methyltransferase inhibition and ligand-enzyme docking scores
- Reported
- Activity spanned more than a thousand-fold across the series; quinoliniums reached low micromolar inhibition near 1 micromolar, and docking scores correlated with the measured IC50 values. [1]
In vitro
- System
- Parallel artificial membrane permeability and Caco-2 cell assays, plus selectivity panels of related methyltransferases and NAD+ salvage pathway enzymes
- Measured
- Membrane permeability and off-target enzyme inhibition for methylquinolinium analogues with primary amine substitutions
- Reported
- Permeability was high by both passive and active transport, and the analogues did not inhibit the related methyltransferases or the NAD+ salvage enzymes tested. [2]
In vitro
- System
- Cultured adipocytes
- Measured
- Intracellular 1-methylnicotinamide, NAD+ and S-adenosylmethionine levels, and lipogenesis
- Reported
- The reaction product fell while NAD+ and S-adenosylmethionine rose, and lipogenesis was suppressed. [2]
Preclinical in vivo
- System
- Diet-induced obese mice fed a high-fat diet
- Measured
- Body weight, white adipose mass, adipocyte size, plasma total cholesterol and food intake
- Reported
- Body weight, white adipose mass, adipocyte size and plasma total cholesterol all fell, while total food intake was unchanged. [2]
In vitro
- System
- C2C12 myoblast cultures
- Measured
- Myoblast differentiation and the cellular NAD+ to NADH redox state
- Reported
- Differentiation was promoted and enhanced, with supporting changes in the redox state. [3]
Preclinical in vivo
- System
- 24-month-old mice given a local barium chloride muscle injury, with 5-ethynyl-2'-deoxyuridine labelling of muscle stem cells
- Measured
- Muscle stem cell proliferation and fusion, myofiber cross-sectional area, fiber size distribution and in vivo contractile torque
- Reported
- Stem cell proliferation and fusion rose, cross-sectional area was nearly two-fold greater with a shift toward larger fibers, and peak torque of the tibialis anterior was about 70 percent greater than in controls. [3]
In vitro
- System
- HeLa cervical carcinoma cells with HEK-293 cells as a comparison line; the authors abbreviate the compound 5MQ and identify it as 5-amino-1-methylquinolinium
- Measured
- Viability by MTT assay, cell morphology, and TWIST, ZEB1, SERPIN1, SIRT1 and CD16 transcript and protein levels
- Reported
- Proliferation was inhibited in a concentration and time dependent manner in HeLa cells without apparently affecting HEK-293 proliferation; ZEB1, SIRT1 and CD16 transcripts rose while TWIST and SERPIN1 fell, and phospho-Akt and SIRT1 protein fell. [5]
Preclinical in vivo
- System
- Diet-induced obese mice switched to a low-fat diet, with cecal microbiome sequencing and age-matched lean controls
- Measured
- Cecal microbiome composition by amplicon sequence variant clustering, alpha and beta diversity, and correlation with adipose tissue metabolites
- Reported
- The inhibitor-treated group formed a distinct cluster, with lower Erysipelatoclostridium and higher Lactobacillus relative abundance than vehicle counterparts, while alpha diversity did not differ significantly between groups. [6]
Handling for in-vitro work
- Solubility in the cited work
- Permeability was characterized in parallel artificial membrane and Caco-2 cell assays, so the assay medium and the membrane model are part of the method record for this scaffold [2]
- Selectivity controls
- The cited selectivity panel covered related S-adenosylmethionine-dependent methyltransferases and NAD+ salvage pathway enzymes; those controls belong with any new enzyme assay using this scaffold [2]
- Storage
- Solid material kept dry, dark and cold; solutions prepared fresh and used promptly
Open questions
- Two of the cited reports describe the series generically as methylquinolinium analogues with primary amine substitutions rather than naming this compound, so matching a supplied material to the exact analogue in those papers requires an analytical identity, not the series name.
- One cited report writes the abbreviation out as 5-methylquinolinium in its opening line and as 5-amino-1-methylquinolinium in its impact statement, an inconsistency the abstract does not resolve.
- The cited work does not report the counterion or salt form, so the nominal mass of a supplied material cannot be checked against these papers.
Lot records
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No published lot is available for this exact compound name.
Read a certificate of analysis ↗References
- Neelakantan H, Wang HY, Vance V, et al. Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. Journal of medicinal chemistry. 2017.
- Neelakantan H, Vance V, Wetzel MD, et al. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochemical pharmacology. 2018.
- Neelakantan H, Brightwell CR, Graber TG, et al. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochemical pharmacology. 2019.
- Kannt A, Rajagopal S, Kadnur SV, et al. A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders. Scientific reports. 2018.
- Akar S, Duran T, Azzawri AA, et al. Small molecule inhibitor of nicotinamide N-methyltransferase shows anti-proliferative activity in HeLa cells. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2021.
- Dimet-Wiley A, Wu Q, Wiley JT, et al. Reduced calorie diet combined with NNMT inhibition establishes a distinct microbiome in DIO mice. Scientific reports. 2022.
Publication records fetched from PubMed on 2026-09-20. Profile text reviewed 2026-09-20.