5-Amino-1MQ

Even though it often sits next to peptides, 5-Amino-1MQ, in full 5-amino-1-methylquinolinium, is a small, orally bioavailable molecule. Its target is the enzyme nicotinamide N-methyltransferase, NNMT for short.

What NNMT does and why it matters:

• The enzyme is present at high levels in visceral adipose tissue.
• There it transfers a methyl group onto nicotinamide, a form of vitamin B3, turning it into 1-methylnicotinamide.
• The methyl donor is S-adenosylmethionine (SAM); the reaction uses up SAM and shrinks the available NAD+ pool.
• Preclinically, high NNMT activity is tied to enlarged fat cells and a throttled energy metabolism; knocking the enzyme down protected mice from diet-induced obesity.

What inhibition by 5-Amino-1MQ does in research models:

• More NAD+ and more SAM in adipocytes, with the methyl pool spared.
• Stronger mitochondrial activity, more lipolysis, smaller fat cells in mouse models.
• In obese mice, body weight and white adipose tissue went down without any change in food intake.

From the chemistry: in the 2017 structure-activity analysis, quinolinium compounds, the class 5-Amino-1MQ belongs to, were the most potent inhibitors with inhibitory concentrations around 1 µM. A further mouse study found, in 24-month-old animals after muscle injury, more active muscle stem cells, nearly twice the fiber cross-section and about 70 percent more torque. For research, the molecule is above all a tool for metabolic flexibility and the NAD+ axis; because it is taken orally, the experimental setup differs from that for peptides.

In the preclinical data, 5-Amino-1MQ shows no pronounced toxicity profile and counts as well tolerated according to the studies; as an orally taken small molecule, the picture differs from that of injectable peptides.

• Digestion: occasional mentions of mild stomach or gut discomfort, for instance unease or nausea.
• Metabolism: NNMT inhibition shifts the NAD+ and methyl pools in research models, and what that means over the long run has not been fully examined.
• Energy and sleep: isolated reports describe altered energy levels or altered sleep, with a thin data base behind them.
• Human data: robust human studies are practically absent, everything rests on cell and mouse models.

This summary is no substitute for medical advice.

• Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity - the 2014 paper describing NNMT knockdown in the mouse model.
• Structure-Activity Relationship for Small Molecule Inhibitors of NNMT - the structure-activity analysis in which the quinolinium class led with inhibitory concentrations around 1 µM.
• Membrane-permeable small molecule NNMT inhibitors reverse diet-induced obesity in mice - membrane-permeable, selective methylquinolinium inhibitors: more NAD+ and SAM in adipocytes, less lipogenesis, less weight and white fat in obese mice.
• NNMT inhibitor activates senescent muscle stem cells in aged skeletal muscle - the study in 24-month-old mice covering stem cell activity, fiber cross-section and torque.