5-Amino-1MQ

5-Amino-1MQ (5-amino-1-methylquinolinium) came out of a University of Texas programme that screened small quinolinium molecules against NNMT. The quinoliniums were the most potent scaffold, inhibiting the enzyme at around 1 µM [1]. 5-Amino-1MQ crossed cell membranes well, did not inhibit related methyltransferases or NAD+ salvage enzymes, and was chosen for animal work [3].

Obesity and fatty liver in mice.

• In diet-induced obese mice given 20 mg/kg three times a day for 11 days, controls gained about 1.4% of body weight and treated mice lost about 5.1%. Food intake did not differ, fat pads and fat cells were smaller, and plasma cholesterol was lower [3].
• Over 30 days, 32 mg/kg once daily held weight gain to 0.9 g against 5.4 g in controls. It also improved glucose tolerance, reduced fatty liver and normalised liver enzymes. The 10 mg/kg dose did not limit weight gain [4].
• Added to a switch from a high-fat to a lean diet, it roughly doubled weight loss and increased fat loss about tenfold compared with the diet switch alone (about 29% versus 3% of fat mass) [7].

Ageing muscle in mice. In 24-month-old mice with an injured leg muscle, treatment increased muscle stem cell activity, nearly doubled the size of regenerating fibres and raised peak torque by about 70% [5]. In a later study, 8 weeks of treatment gave old sedentary mice about 40% more grip strength than controls, against 20% for exercise alone and 60% for the two combined [6].

Human evidence. None. No trial has given 5-amino-1MQ to people. A 2026 review of NNMT inhibitors says the field has been held back by weak target engagement, poor bioavailability and unknown safety, and that newer compounds are trying to fix this [8].

Who did the research. Almost every study above comes from the same University of Texas group. Several authors are employees or founders of Ridgeline Therapeutics, which develops NNMT inhibitors [4][6][7].

NNMT transfers a methyl group from S-adenosylmethionine (SAM) to nicotinamide, a form of vitamin B3. The product, 1-methylnicotinamide, cannot be recycled into NAD+. In mice, NNMT is more active in the fat and liver of obese animals, and knocking the enzyme down with antisense drugs protected against diet-induced obesity by raising energy expenditure. Fat tissue SAM and NAD+ rose [2]. Knocking out the gene gave a less clear picture. It improved insulin sensitivity in male mice on a high-fat diet, and cut weight gain in female mice on a Western diet, but did not improve glucose tolerance [9].

5-Amino-1MQ is meant to copy the knockdown with a drug. In fat cells in culture it lowered 1-methylnicotinamide, raised NAD+ and SAM, and suppressed fat synthesis [3]. In muscle cells it shifted the NAD+/NADH balance and promoted differentiation [5]. After injection in mice it reached fat, muscle and liver. At 1 hour after a dose, 1-methylnicotinamide was about 70% lower in fat and 40% lower in muscle, and levels recovered within hours [4].

The oral data conflict. A rat study reported 38.4% oral bioavailability [10]. A later mouse study from the developers found only 3.5%, with a peak blood level about 500 times lower than after a similar injected dose. The authors blamed poor absorption from the gut and fast breakdown in the liver [4]. Every efficacy study in mice used injections under the skin [3][4][6].

There are no human safety data. In a small dose-escalation in two obese mice (10 up to 150 mg/kg a day), 60 mg/kg a day was well tolerated with no visible adverse effects [3]. Twice-daily dosing in 24-month-old mice caused no systemic toxicity or behavioural changes [5]. At the highest concentration tested (600 µM) it killed about 40% of fat-precursor cells in culture [3].

NNMT also methylates drugs and other foreign compounds [1], so inhibiting it could in principle change how they are handled. This has not been studied.