5-Amino-1MQ
5-Amino-1-methylquinolinium (NNMT inhibitor)
Small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT), the enzyme that methylates nicotinamide and removes it from the NAD+ salvage pathway. NNMT is overexpressed in the white adipose tissue and aged skeletal muscle of obese and old animals, and knocking it down protects mice from diet-induced obesity (Kraus 2014, Nature). 5-Amino-1MQ is the membrane-permeable quinolinium that came out of the Watowich lab at UT Medical Branch and is the molecule sold to consumers as an oral capsule. The honest position on evidence: there is no published human trial of 5-Amino-1MQ, or of any NNMT inhibitor, at any dose or by any route. Every result below is in mice. Note also that the mouse studies which produced the fat-loss and muscle-regeneration findings injected the compound subcutaneously, so the oral capsule that is actually sold rests on cell-permeability assays (Caco-2, no detectable efflux) rather than on a published in-vivo oral result.
At a glance
- Routes
- Oral · SubQ
- Evidence base
- 4 studies 4 preclinical
Mechanism
NNMT consumes nicotinamide and a methyl group from S-adenosylmethionine (SAM) to produce 1-methylnicotinamide (1-MNA). Every nicotinamide molecule methylated is one that cannot be recycled back to NAD+ by NAMPT. Inhibiting NNMT therefore raises intracellular NAD+ and SAM at the same time: in cultured adipocytes 5-Amino-1MQ lowered 1-MNA, raised NAD+ and SAM, and suppressed lipogenesis (Neelakantan 2018). This is the mechanistic opposite of NMN and NR, which push substrate in from outside rather than stopping the leak. Downstream, restored NAD+ supports sirtuin-1 activity; Kraus 2014 attributed the anti-obesity effect of NNMT knockdown to increased cellular energy expenditure and polyamine flux rather than to appetite suppression, which matches the observation that treated mice did not eat less. Selectivity screening found no inhibition of the related SAM-dependent methyltransferases DNMT1, PRMT3 and COMT, nor of the NAD+ salvage enzymes NAMPT and SIRT1.
Dosing
No standardized human dosing has been established. Every catalogued study for 5-Amino-1MQ is preclinical or a literature review. Amounts used in animal models do not translate directly to humans.
Where a study reports an amount, it appears in that study's entry below, attributed to the source.
Published evidence
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Animal in vivo 2022
Reduced calorie diet combined with NNMT inhibition establishes a distinct microbiome in DIO mice
Diet-induced obese mice given 5-Amino-1MQ alongside a switch to low-fat diet normalized adiposity and body weight to age-matched lean animals faster than the diet switch alone. Treated mice showed a distinct cecal microbiome, with lower Erysipelatoclostridium and higher Lactobacillus. The primary endpoint was the microbiome, not weight; author affiliations include the company developing the molecule.
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Animal in vivo 2019
Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle
24-month-old mice with barium chloride injury to the tibialis anterior, treated with NNMT inhibitor at 5 or 10 mg/kg for 1 week or 3 weeks post-injury. Muscle stem cell proliferation and fusion increased, myofiber cross-sectional area was nearly 2-fold greater than control, and peak torque of the injured muscle was about 70% higher. First evidence that NNMT inhibition rescues aged muscle regeneration.
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Animal in vivo 2018
Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice
Diet-induced obese mice, n=9 per cohort, 5-Amino-1MQ 20 mg/kg subcutaneously three times a day (about 34 mg/kg/day) for 11 days. Progressive body-weight loss versus saline, reduced epididymal fat pad mass and adipocyte size, lower plasma total cholesterol, and no change in food intake. In adipocytes the compound lowered 1-MNA, raised NAD+ and SAM and suppressed lipogenesis, with no inhibition of DNMT1, PRMT3, COMT, NAMPT or SIRT1. The foundational in-vivo result for this molecule.
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Animal in vivo 2014
Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity
Nnmt antisense knockdown in mouse white adipose tissue and liver protected against diet-induced obesity by increasing cellular energy expenditure. Adipose SAM and NAD+ rose, polyamine flux increased (confirmed by urinary and adipocyte diacetylspermine), and histone H3 lysine 4 methylation changed in adipose tissue. Target validation for the whole NNMT-inhibitor class; uses genetic knockdown, not this molecule.
Reported side effects
- No human safety data exists
- Unknown Moderate · No published human trial of 5-Amino-1MQ or of any NNMT inhibitor. There is no characterized adverse-event profile, no maximum tolerated exposure and no drug-interaction data in humans. Everything circulating is uncontrolled self-report.
- Tolerated in rodent dosing
- Unknown Mild · Neelakantan 2018 reported no observable adverse effects in diet-induced obese mice, including in a dose-escalation arm, and no change in food intake at the exposure that produced weight loss. Rodent tolerability over 11 days establishes nothing about human safety.
- Methylation flux shift (theoretical)
- Theoretical Moderate · NNMT inhibition raises intracellular SAM, the universal methyl donor for DNA and histone methylation. Kraus 2014 showed NNMT knockdown changes histone H3 lysine 4 methylation in adipose tissue. Redirecting methyl flux is the mechanism of action, so it is not an off-target effect, but the long-term consequences in humans are entirely uncharacterized.
- Reduced 1-MNA (theoretical)
- Theoretical Mild · 1-methylnicotinamide, the product the enzyme makes, has vasodilatory and anti-inflammatory activity of its own. Suppressing it is an intended consequence of inhibiting NNMT, and whether that is neutral has not been tested.
Interactions
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NMN Synergy
Opposite ends of the same pathway. NNMT inhibition stops nicotinamide being methylated away, while NMN supplies substrate from outside. Mechanistically complementary and never tested together in any species.
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NAD+ Synergy
Same pathway from both directions: NNMT inhibition preserves the recycling arm while injected NAD+ floods the salvage arm with substrate. No combination data exists.
Storage
Capsules: room temperature, dry, dark. The quinolinium salt is stable as a solid. Product quality varies widely and third-party HPLC purity documentation is the only check available, since there is no pharmacopoeial monograph for this molecule.