5-Amino 1MQ

How 5-Amino 1MQ is described to act.

5-Amino-1-methylquinolinium (5-amino-1MQ, 5A1MQ, 5-AMQ) is a small-molecule, membrane-permeable inhibitor of nicotinamide N-methyltransferase (NNMT), the cytosolic enzyme that transfers a methyl group from S-adenosyl-L-methionine to nicotinamide to form 1-methylnicotinamide. Structure-activity work screening N-methylated quinolinium, isoquinolinium, pyridinium and benzimidazolium/benzothiazolium analogues identified quinoliniums as a scaffold reaching low-micromolar IC50 values, with computational docking placing them at the NNMT nicotinamide substrate-binding site. Because nicotinamide is the entry substrate of the NAD+ salvage pathway, NNMT inhibition is described in this literature as intersecting with NAD+ salvage flux and sirtuin 1 activity. NNMT is reported to be overexpressed in adipose tissue and skeletal muscle in rodent obesity and aging models, which is the stated rationale for targeting it in those tissues.

Mechanistic descriptions summarize published in vitro and animal work. They are not a representation of efficacy or safety in any subject, and no administration guidance is given or implied.

In diet-induced obese mice, once-daily 5A1MQ over 28 days dose-dependently limited body weight and fat mass gain, altered oral glucose tolerance and insulin measures, and attenuated hepatic steatosis, macrophage infiltration, liver weight and hepatic triglycerides on histology, with plasma and tissue pharmacokinetics characterized after intravenous, oral and subcutaneous dosing. An earlier report in the same series characterized membrane permeability by parallel artificial membrane permeability and Caco-2 assays, selectivity against structurally related methyltransferases and NAD+ salvage pathway enzymes, and effects on lipogenesis and intracellular 1-methylnicotinamide in cultured adipocytes before testing in diet-induced obese mice. In 24-month-old mice, NNMT inhibitor treatment was reported to activate senescent muscle stem cells and increase regenerative capacity after injury, and a separate study in 22-to-24-month-old mice compared NNMT inhibition, intensive exercise and their combination across grip strength, longitudinal running capacity, plantarflexor peak torque, fibre cross-sectional area and intramyocellular lipid, with proteome and metabolome profiling. A validated LC-MS/MS assay was developed to quantify 5-AMQ in rat plasma and urine for pharmacokinetic and oral bioavailability determination. The literature on this compound is small and, within this citation set, entirely preclinical and in vitro; no human clinical trial is represented.

Sources & references

Cited literature is provided for scientific reference only and does not constitute a representation of efficacy or safety in any subject. All research findings presented are sourced from peer-reviewed journals and are provided for educational reference only.

1. 01
   Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction

   Babula JJ, et al. · Diabetes Obes Metab, 2024

   PMID 39161060DOI 10.1111/dom.15879

2. 02
   Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice

   Dimet-Wiley AL, et al. · Sci Rep, 2024

   PMID 38969654DOI 10.1038/s41598-024-66034-9

3. 03
   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, et al. · J Pharm Biomed Anal, 2021

   PMID 34304009DOI 10.1016/j.jpba.2021.114255

4. 04
   Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle

   Neelakantan H, et al. · Biochem Pharmacol, 2019

   PMID 30753815DOI 10.1016/j.bcp.2019.02.008

5. 05
   Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice

   Neelakantan H, et al. · Biochem Pharmacol, 2018

   PMID 29155147DOI 10.1016/j.bcp.2017.11.007

6. 06
   Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase

   Neelakantan H, et al. · J Med Chem, 2017

   PMID 28548833DOI 10.1021/acs.jmedchem.7b00389

Every entry links to its record at the publisher or on PubMed. Titles are reproduced exactly as published.