5-Amino-1MQ

Key Benefits

Preserves NAD⁺ Salvage

By inhibiting NNMT, less nicotinamide is converted to 1-methylnicotinamide (1-MNA), leaving more substrate available to run the NAMPT → NMN → NMNAT → NAD⁺ salvage route.

Improves “methyl-economy” by sparing SAM

NNMT consumes SAM and generates SAH while methylating nicotinamide. Inhibiting NNMT increases intracellular SAM and changes the SAM/SAH balance, which can ripple into global methylation capacity and polyamine flux.

Reduced Lipid Accumulation

In 3T3-L1 differentiation models, 5-Amino-1MQ caused concentration-dependent suppression of lipid accumulation/lipogenesis.

In vivo phenotype

Fat-mass reduction without eating less (mouse DIO model)
In diet-induced obese mice, repeated subcutaneous dosing produced progressive weight loss, reduced epididymal fat pad mass, smaller adipocytes, and improved lipid profile markers

Biologic Description

Primary target (not a receptor)

Target: NNMT (nicotinamide N-methyltransferase) — a cytosolic enzyme that catalyzes methyl transfer from SAM → SAH onto nicotinamide, forming 1-MNA.
Mechanism class: NAM-site competitive inhibitor (acts at the nicotinamide binding site; described in NNMT inhibitor reviews).

Core biochemical consequences of NNMT inhibition

NAD⁺ salvage shunting
- With NNMT blocked, nicotinamide is less “disposed” into 1-MNA, increasing availability for:
  - NAMPT (rate-limiting step): NAM + PRPP → NMN
  - NMNAT: NMN → NAD⁺
- NAD⁺ then feeds:
  - Sirtuins (e.g., SIRT1)
  - PARPs
  - CD38 (major NADase in many tissues)
    In adipocytes, 5-Amino-1MQ treatment increased NAD⁺ and altered NA/SAM/SAH metabolite levels consistent with this shunt.
Methionine cycle / methyl donor economy
- NNMT is sometimes framed as a “methyl sink” because it can drain SAM while generating SAH.
- Inhibiting NNMT increases intracellular SAM (shown in adipocytes), which can influence:
  - SAM-dependent methyltransferases (DNA, histone, small molecules)
  - Polyamine metabolism (SAM decarboxylation contributes to spermidine/spermine synthesis)
Metabolic phenotype links
- NNMT activity is associated (in various models/reviews) with energy expenditure and fat storage vs oxidation, partly via NAD⁺ availability and downstream redox/mitochondrial signaling.

Potency + permeability

5-Amino-1MQ is notable among early NNMT inhibitors for being both potent and membrane-permeable:
- NNMT inhibition IC₅₀ ~ 1.2 µM (reported in the inhibitor series table).
- High permeability in PAMPA and Caco-2 transport assays; no strong efflux signal noted.

Selectivity / off-target screening (important for your “pathway credibility”)

In the cited dataset, 5-Amino-1MQ showed little/no inhibition of:
- DNMT1, PRMT3, COMT at tested concentrations
- NAMPT and SIRT1 (no meaningful inhibition across most tested ranges; assay interference at high concentrations was noted for NAMPT readout).

Dosage Guidelines

Human dosing has not been established in controlled clinical studies. Any discussion of dose translation is provided for educational context only and is not medical advice.

This is a Preclinical Dosing Context + Human-Equivalent Dose (HED) math.

Preclinical dosing used in key studies

Diet-induced obese mice (SC injections, 11 days):
20 mg/kg three times daily (t.i.d.) SC injections; authors report ~34 mg/kg/day total parent compound exposure.
Aged mice muscle function study (SC daily, 8 weeks):
10 mg/kg body weight daily SC dosing.

Optional: HED conversion (for context only)

FDA describes body-surface-area scaling approaches for translating animal doses to human equivalents.
Using common BSA scaling conventions (mouse → human), those mouse doses correspond roughly to:

10 mg/kg (mouse) → ~0.8 mg/kg (human equivalent)
34 mg/kg/day (mouse) → ~2.8 mg/kg/day (human equivalent)

But: HED ≠ safe starting dose, and it definitely doesn’t account for formulation, route (SC vs oral), salt form, PK, toxicity limits, etc.

100-200mcg

1-2 x Week

4-6 Weeks

Side Effects

Observed in the mouse obesity model

In the 11-day DIO mouse study, a dose escalation up to 60 mg/kg/day was reported as well tolerated with no observable adverse effects, and the main treatment period also reported no obvious adverse effects.

Cell toxicity window (important)

In the adipocyte work, intracellular 1-MNA suppression plateaued by ~10–60 µM, and higher concentrations weren’t pursued due to known cytotoxic effects in 3T3-L1 cells; modest cytotoxicity was noted at higher (100–300 µM) ranges in viability assays.

Mechanism-based risks (the “might bite you later” list)

These are biologically plausible concerns from NNMT biology (not proven human outcomes):

Methylation balance shifts: Altered SAM/SAH dynamics could affect epigenetic methylation patterns and methyl-dependent pathways.
Nicotinamide accumulation effects: Blocking NNMT can raise NAM availability; NAM itself can modulate NAD-dependent enzymes indirectly (context dependent).
Oxidative stress signals in some cancer cell lines: At least one NNMT inhibitor paper reports changes consistent with increased ROS in treated cancer lines (context: oncology cell models).

Populations where you should be extra conservative

People on methylation-active meds/supps (high-dose methyl donors, etc.)
Cancer / immunotherapy contexts (NNMT is implicated in tumor microenvironment biology; NNMT inhibition has been explored experimentally in cancer models)
Liver/kidney impairment (clearance unknown in humans; don’t pretend)

References:

Neelakantan H, Vance V, Wetzel MD, et al. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochemical Pharmacology. 2018;147:141–152. (PMCID: PMC5826726).
Dimet-Wiley AL, Latham CM, Brightwell CR, et al. Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice. Scientific Reports. 2024;14:15554. doi:10.1038/s41598-024-66034-9.
Liu JR, Miao H, Deng D, Vaziri ND. Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes. Journal of Diabetes Research. 2021;2021:9924314. (PMCID: PMC8337113).
Iyamu ID, Perdew H, Woods G, et al. Mechanisms and inhibitors of nicotinamide N-methyltransferase (NNMT): A structure-function perspective. Biochemical Pharmacology. 2021. (Review; PMCID: PMC8372200).
Dimet-Wiley A, et al. Reduced calorie diet combined with NNMT inhibition establishes a distinct microbiome in diet-induced obese mice. Scientific Reports. 2022.
Yang M, et al. NAD⁺ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer. Journal for ImmunoTherapy of Cancer. 2024;12:e009281.
U.S. Food and Drug Administration (FDA). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. 2005.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy. 2016;7(2):27–31.

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