5-amino-1MQ

What is 5-amino-1MQ?

Obesity may significantly impact one’s quality of life, as it can negatively affect independent movement and exercise. While this condition can cause physical and emotional problems, it can also increase one’s risk for deadly diseases such as heart problems, diabetes, cancer, stroke, and non-alcoholic liver failure. Unfortunately, once you become obese, this condition is extremely difficult to reverse or even treat effectively. This is because obesity affects the body’s ability to break down fat stores and use them as a source of energy. In fact, even drugs that have been designed to boost fat breakdown may be ineffective. Therefore, body fat accumulates over time and becomes very challenging to remove without surgical intervention.

Recently, a new breakthrough may help patients with this severe form of obesity achieve a healthier weight. The NNMT inhibitor 5-amino-1-methylquinoline or 5-amino-1MQ has been shown to reduce the production of the enzyme nicotinamide N-methyltransferase (NNMT), a regulator of energy homeostasis in adipose tissue (a type of fat used for energy storage). This mechanism could shrink white adipose tissue and dramatically reduce weight without the need to limit calorie intake.

How 5-amino-1MQ Works

5-amino-1MQ blocks the activity of an enzyme called nicotinamide N-methyltransferase (NNMT). This process stimulates an increase in the levels of nicotinamide adenine dinucleotide (NAD+), which is involved in a wide array of cellular reactions. The increase in NAD+ levels also increases the body’s metabolic rate, resulting in weight loss. In addition, a gene called sirtuin-1 (SIRT1), also known as ‘the longevity gene’, is also activated. SIRT1 helps lower the risk of debilitating diseases such as diabetes, cardiovascular disease, and cancer.

Chemical Structure of 5-amino-1MQ

Research on 5-amino-1MQ

Produces Dramatic Weight Loss

Evidence suggests that by shrinking white adipose tissue, 5-amino-1MQ can significantly reduce weight and improve body composition:

1. In U.S. Veterans military service members, the administration of 5-amino-1MQ resulted in significant weight loss without any adverse side effects. [1]
2. In diet-induced obese mice that were maintained on a high-fat diet, the administration of an NNMT inhibitor significantly reduced body weight and white adipose tissue mass and decreased the size of adipocyte cells (cells specialized for fat storage) without any observable adverse effects. [2-3]
3. The administration of an NNMT inhibitor in mice on a high-fat diet (HFD) protected against fat accumulation by augmenting cellular energy expenditure. [4]
4. Studies also showed that NNMT is increased 2-fold in the subcutaneous and abdominal adipose tissue of type 2 diabetic men and women compared to healthy subjects, suggesting that the administration of NNMT inhibitors may reduce body fat. [5-7]
5. A cell study found that 5-amino-1MQ prevented lipogenesis (fat formation). [8]
6. Studies found that high levels of NNMT were often found in fat cells and were associated with impaired calorie utilization resulting in increased fat storage. [9-10]

Lowers Cholesterol Levels

Studies show that 5-amino-1MQ’s ability to increase NAD+ and activate the SIRT1 gene can help improve cholesterol levels:

1. In diet-induced obese (DIO) mice maintained on a high-fat diet, the administration of an NNMT inhibitor lowered plasma total cholesterol levels. [3]
2. A study found that SIRT1 activation by 5-amino-1MQ resulted in the suppression of cholesterol synthesis. [11]

Improves Blood Sugar Levels

Evidence also found that 5-amino-1MQ has beneficial effects on blood sugar levels:

1. In diet-induced obese (DIO) mice maintained on a high-fat diet, the administration of a potent NNMT inhibitor dramatically reduced blood sugar levels without altering food intake and without adverse side effects. [3]
2. Several studies found that NNMT plays a causative role in the development of type 2 diabetes and insulin resistance, suggesting that NNMT inhibitors may help lower the risk of the disease. [12-16]
3. In mice, 5-amino-1MQ altered how fat cells work leading to the production of palmitic acid esters of hydroxy-stearic acids (PAHSAs), a class of lipids that can reduce insulin resistance. [17]

Fights Inflammation

Evidence suggests that the enzyme NNMT is highly associated with inflammatory conditions and related injuries, suggesting that NNMT inhibitors like 5-amino-1MQ may have an anti-inflammatory role:

1. Significantly increased levels of NNMT have been observed in the lungs and skeletal muscle of patients with chronic obstructive pulmonary disease (COPD) with muscle wasting. [18-19]
2. Experimental studies in mice also found an increase in NNMT levels after drug-induced liver injury. [20-21]
3. A study found that NNMT production is the body’s protective compensatory response to injury, resulting in inflammatory states. [22]

Combats Various Cancer Types

A number of high-quality studies also suggest that high levels of NNMT are strongly linked with the development of various types of cancer, suggesting a potential therapeutic role for NNMT inhibitors:

1. NNMT levels are significantly increased in primary glioblastoma tumors (aggressive brain tumors) compared to normal human brain samples. [23]
2. Enhanced NNMT production is also increased in human papillary thyroid cancer cell lines. [24]
3. In renal clear cell carcinoma, NNMT production is also significantly increased. [25]
4. In human bladder cancer, NNMT was found to be a major regulator of cell migration. [26]
5. The NNMT protein is also increased in gastric cancers. [27-28]
6. NNMT is also identified as a novel serum tumor marker for human colorectal cancers and oral squamous cell carcinoma. [29-30]
7. NNMT knockdown (NNMT gene loss) decreased the proliferation and migration of bladder cancer cells. [31]
8. NNMT knockdown also inhibited the proliferation and/or metastasis of kidney cancer cells, pancreatic cancer cells, and oral squamous carcinoma. [32-34]
9. In non-small-cell lung cancer cells, inhibition of NNMT production resulted in suppression of tumor growth. [35]
10. Higher levels of NNMT in tumor tissues are associated with lower overall survival rates in cancer patients, suggesting that NNMT inhibitor administration may help improve survival. [36]
11. In a human oral cancer cell line, the administration of an NNMT inhibitor dramatically reduced cancer cell growth and reproduction. [37]

Enhances Aged Muscle Regeneration

Studies suggest that 5-amino-1MQ and other NNMT inhibitors have the potential to treat age-related muscle weakness:

1. In old mice (24 months) with acute muscle injury due to barium chloride injection, the NNMT inhibitor-treated group exhibited greater contractile function (indicative of improved muscle function) compared to the saline-treated group. [38]
2. In a mouse model of muscular dystrophy (progressive weakness and loss of muscle mass), NAD+ restoration delayed muscle deterioration and increased mouse life span. [39]
3. In mice with muscular dystrophy, replenishing NAD+ stores with dietary nicotinamide riboside supplementation improved muscle and heart function. [40]
4. A study found that increased NNMT was commonly associated with muscle wasting disorders, suggesting that NNMT inhibitors like 5-amino-1MQ may provide benefit. [41]

Associated Side Effects of 5-amino-1MQ

5-amino-1MQ side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on 5-amino-1MQ. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of 5-amino-1MQ. Despite this, it was listed as a side effect associated with 5-amino-1MQ even though these associated side effects are very uncommon.
Side effects associated with 5-amino-1MQ may include the following:

• Difficulty sleeping
• Difficulty participating in exercise

References:

1. Available from https://apps.dtic.mil/dtic/tr/fulltext/u2/1059191.pdf.
2. Available from https://diabetes.diabetesjournals.org/content/67/Supplement_1/115-LB.
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4. Kraus D, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014; 508:258–262.
5. Kannt A, et al. Association of nicotinamide-N-methyltransferase mRNA expression in humanadipose tissue and the plasma concentration of its product, 1-methylnicotinamide, with insulinresistance. Diabetologia. 2015; doi: 10.1007/s00125-014-3490-7.
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17. Moraes-Vieira, P. M., Saghatelian, A., & Kahn, B. B. (2016). GLUT4 Expression in Adipocytes Regulates De Novo Lipogenesis and Levels of a Novel Class of Lipids With Antidiabetic and Anti-inflammatory Effects. Diabetes, 65(7), 1808–1815. https://doi.org/10.2337/db16-0221.
18. Kim HC, et al. Expression and functional significance of nicotinamide N-methyl transferase inskeletal muscles of patients with chronic obstructive pulmonary disease. Am J RespirCrit CareMed. 2010; 181:797–805.
19. Savarimuthu Francis SM, et al. Genes and gene ontologies common to airflow obstruction andemphysema in the lungs of patients with COPD. PloS One. 2011; 6:e17442.
20. Sternak M, et al. Nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA) in experimental hepatitis induced by concanavalin A in the mouse. Pharmacol Rep PR. 2010;62:483–493.
21. Fedorowicz A, et al. Activation of the nicotinamide N-methyltransferase (NNMT)-1-methylnicotinamide (MNA) pathway in pulmonary hypertension. Respir Res. 2016; 17:108.
22. Jakubowski A, et al. 1-Methylnicotinamide protects against liver injury induced by concanavalin Avia a prostacyclin-dependent mechanism: A possible involvement of IL-4 and TNF-α. IntImmunopharmacol. 2016; 31:98–104.
23. Markert JM, et al. Differential gene expression profiling in human brain tumors. Physiol Genomics. 2001;5:21–33.
24. Xu J, et al. Enhanced expression of nicotinamide N-methyltransferase in human papillary thyroid carcinoma cells. J ClinEndocrinolMetab. 2003;88:4990–4996.
25. Yao M, et al. Gene expression analysis of renal carcinoma: adipose differentiation-related protein as a potential diagnostic and prognostic biomarker for clear-cell renal carcinoma. J Pathol. 2005;205:377–387.
26. Wu Y, et al. Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration. Oncogene. 2008;27:6679–6689.
27. Jang JS, et al. The differential proteome profile of stomach cancer: identification of the biomarker candidates. Oncol Res. 2004;14:491–499.
28. Lim BH, et al. Overexpression of nicotinamide N-methyltransferase in gastric cancer tissues and its potential post-translational modification. ExpMol Med. 2006;38:455–465.
29. Roessler M, et al. Identification of nicotinamide N-methyltransferase as a novel serum tumor marker for colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:6550–6557.
30. Sartini D, et al. Nicotinamide N-methyltransferaseupregulation inversely correlates with lymph node metastasis in oral squamous cell carcinoma. Mol Med Camb Mass. 2007;13:415–421.
31. Wu Y, et al. Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration. Oncogene. 2008;27:6679–6689.
32. Yu T, et al. Effects of nicotinamide N-methyltransferase on PANC-1 cells proliferation, metastatic potential and survival under metabolic stress. Cell PhysiolBiochemInt J Exp Cell PhysiolBiochemPharmacol. 2015;35:710–721.
33. Tang SW, et al. Nicotinamide N-methyltransferase induces cellular invasion through activating matrix metalloproteinase-2 expression in clear cell renal cell carcinoma cells. Carcinogenesis. 2011;32:138–145.
34. Pozzi V, et al. RNA-mediated gene silencing of nicotinamide N-methyltransferase is associated with decreased tumorigenicity in human oral carcinoma cells. PloS One. 2013;8:e71272.
35. Bach DH, Kim D, Bae SY, et al. Targeting Nicotinamide N-Methyltransferase and miR-449a in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer Cells. MolTher Nucleic Acids. 2018;11:455–467. doi:10.1016/j.omtn.2018.03.011.
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37. Gao Y, Van haren MJ, Moret EE, et al. Bisubstrate Inhibitors of Nicotinamide -Methyltransferase (NNMT) with Enhanced Activity. J Med Chem. 2019;62(14):6597-6614.
38. 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. BiochemPharmacol. 2019;163:481-492.
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