Research Dossier  5-amino-1MQ

(Metabolic Modulator)

Classification & Molecular Identity

Chemical Identity

5-amino-1MQ (5-amino-1-methylquinolinium) is a synthetic small molecule belonging to the class of quinolinium derivatives. Unlike peptide bioregulators, which are composed of amino acid chains, this compound is an organic heteroaromatic structure built around the quinoline scaffold. The modification of quinoline at the 1-position with a methyl group and substitution of an amino group at the 5-position confers unique electronic and steric properties that affect biological activity.

• Molecular formula: C₁₀H₁₁N₂⁺

• Molecular weight: ~159 g·mol⁻¹ (cationic core, without counterion)

• Structural motifs: Quinolinium ring, para-amino substituent, methyl substituent at N-1.

• Canonical SMILES (simplified molecular input line entry system): Not fully standardized in all databases, but reported analogs follow quinolinium aromatic notations.

Discovery & Origins

The compound emerged from rational drug-design programs aimed at inhibiting nicotinamide N-methyltransferase (NNMT), an enzyme that regulates cellular methylation balance and links to metabolic disease, obesity, and cancer progression. The earliest reports appear in patent filings and chemical biology literature between 2012 and 2016, where 5-amino-1MQ was identified as a lead scaffold for selective NNMT inhibition.

Endogenous vs. Synthetic

5-amino-1MQ is a fully synthetic small molecule. There is no known endogenous analog in mammalian systems. However, it is designed to mimic transition states and bind to the catalytic pocket of NNMT, competing with nicotinamide substrates.

Homologs, Analogs, Derivatives

• Quinolinium salts: Multiple substituted quinoliniums have been investigated for NNMT inhibition.

• Derivatives: Studies include halogenated, methoxy-, and alkyl-derivatives at the 2-, 4-, and 6-positions.

• Analogs in research: Other NNMT inhibitors such as 1-methylquinolinium iodide and triazole-based scaffolds serve as comparative references.

Historical Development & Research Trajectory

Early Discovery (2012–2016)

Initial focus on NNMT intensified after genomic and proteomic analyses highlighted NNMT overexpression in obesity models and several cancers (including glioblastoma, pancreatic cancer, and hepatocellular carcinoma). Screening of quinolinium analogs led to the identification of 5-amino-1MQ as a potent NNMT inhibitor with cellular activity.

Paradigm Shifts

1. From curiosity to metabolic target: NNMT had previously been viewed as a minor metabolic enzyme. Discovery of its regulatory role in cellular methyl donor balance and NAD⁺ salvage shifted perceptions.

2. Cancer epigenetics link: NNMT’s role in methylation sinks suggested that its inhibition could remodel epigenetic landscapes, influencing tumor progression.

3. Obesity & adipocyte biology: Inhibition of NNMT altered S-adenosylmethionine (SAM) metabolism, enhancing energy expenditure in adipose tissue.

Evolution of Scientific Interest

• 2017–2020: Proof-of-concept studies in mice demonstrated reductions in adiposity and improved metabolic profiles upon treatment with NNMT inhibitors including 5-amino-1MQ.

• 2020 onward: The focus expanded to regenerative biology, oncology, and systemic metabolism, with 5-amino-1MQ frequently cited as a benchmark NNMT inhibitor for experimental use.

Mechanisms of Action

Primary Target: NNMT Inhibition

• NNMT (EC 2.1.1.1): An enzyme that methylates nicotinamide using S-adenosylmethionine (SAM) as the methyl donor.

• 5-amino-1MQ binding: Competes at the nicotinamide-binding pocket, disrupting NNMT activity.

• Result: Elevated intracellular nicotinamide levels, altered NAD⁺ salvage flux, and reduced SAM consumption.

Secondary Effects & Pathways

• Methyl donor balance: Inhibition preserves SAM, increasing global methylation potential.

• Epigenetic regulation: Higher SAM/SAH ratios enhance histone and DNA methylation patterns, impacting gene expression.

• NAD⁺ metabolism: Elevated nicotinamide supports NAD⁺ biosynthesis, indirectly influencing sirtuin and PARP activity.

CNS vs Peripheral Effects

• Peripheral adipose tissue: Demonstrated upregulation of energy expenditure genes, mitochondrial activity, and lipolytic pathways.

• Central nervous system: Limited data. Some studies hypothesize CNS NNMT involvement in Parkinson’s disease and neurodegeneration, but experimental clarity is lacking.

Hormonal, Metabolic, Immune Interactions

• Metabolic: Alters insulin sensitivity in animal models, improves glucose handling.

• Immune: NNMT expression has been linked to macrophage polarization; inhibition may influence inflammatory signaling.

• Hormonal: Indirectly modulates adipokine secretion in obese models.

Evidence Grading

• A (Replicated animal studies): Metabolic and adipose tissue effects.

• B (Preliminary): Epigenetic remodeling, cancer biology impacts.

• C (Hypothesis): CNS roles, immune modulation.

Pharmacokinetics & Stability

Absorption, Distribution, Metabolism, Excretion (ADME)

• Absorption: Data limited; small molecule properties suggest potential for oral bioavailability, but not formally established.

• Distribution: Cationic character suggests tissue localization in mitochondria-rich and negatively charged compartments.

• Metabolism: Likely metabolized via hepatic pathways; detailed enzymatic breakdown unknown.

• Excretion: Not established.

Plasma Half-Life

• Reported as short to moderate in murine models (<12 h).

• Exact values vary depending on formulation and salt form.

Stability

• In vitro: Stable under neutral aqueous conditions.

• In vivo: Prone to clearance through renal or hepatic metabolism.

Storage/Reconstitution

• Research-use vendors recommend cool, desiccated storage.

• Stability post-reconstitution: Not established in peer-reviewed data; typically assumed stable for short-term lab use.

Preclinical Evidence

Animal Studies

• Murine obesity models: Inhibition of NNMT by 5-amino-1MQ reduced body weight gain, adipocyte size, and improved insulin sensitivity (investigational dose: ~10–50 mg·kg⁻¹ in mice, study dependent).

• Cancer cell lines: Reduced proliferation in glioblastoma and pancreatic cancer lines via altered methylation patterns.

In Vitro Studies

• Demonstrated potent inhibition of NNMT at nanomolar to micromolar concentrations.

• Increased intracellular nicotinamide and SAM availability.

Comparative Efficacy

• Outperformed some early triazole inhibitors in potency but had limited pharmacokinetic optimization.

Limitations

• Lack of comprehensive toxicity screens.

• Species-specific differences not resolved.

Human Clinical Evidence

As of September 2025:

• No completed Phase I–III clinical trials are published for 5-amino-1MQ.

• Mentions exist in exploratory patents and research proposals, but ClinicalTrials.gov searches reveal no registered interventional trials specifically for 5-amino-1MQ.

Safety Signals

• Safety in humans: Unknown.

• No reported adverse event data.

Comparative Context

• Related inhibitors: 1-methylquinolinium iodide (less potent), small-molecule triazoles, and bisubstrate NNMT inhibitors.

• Advantages: Simple synthesis, robust in vitro inhibition.

• Disadvantages: Limited pharmacokinetic optimization, uncertain selectivity in vivo.

• Placement: Small-molecule NNMT inhibitor, metabolic research tool.

Research Highlights

• Landmark: 5-amino-1MQ established proof-of-concept for NNMT inhibition as a metabolic intervention (2017).

• Breakthrough: Demonstrated reversal of diet-induced obesity in preclinical mouse models.

• Conflicting evidence: Variability in cancer cell responses; not all lines exhibit sensitivity.

Potential Research Applications

• Metabolism: Study of obesity, insulin resistance, and adipocyte biology.

• Cancer biology: Investigation of epigenetic remodeling and tumor growth.

• Neurobiology: Hypothesized link to neurodegeneration, but evidence preliminary.

• Regenerative medicine: SAM/NAD⁺ modulation may influence stem cell states.

Safety & Toxicology

Preclinical Data

• Rodent studies suggest tolerability at investigational doses (10–50 mg·kg⁻¹).

• No gross organ toxicity reported in limited duration studies.

Molecular Risks

• Altered methylation may produce unpredictable epigenetic consequences.

• Long-term carcinogenicity unknown.

Data Gaps

• No human safety data.

• No chronic exposure studies beyond rodents.

Limitations & Controversies

• Lack of peer-reviewed human studies.

• Conflicting evidence on tumor-suppressive vs tumor-promoting effects depending on cancer type.

• Species-specific differences complicate translational assumptions.

Future Directions

• Medicinal chemistry: Optimization of 5-amino-1MQ derivatives for pharmacokinetics.

• Clinical exploration: Potential Phase I safety studies may emerge within the decade.

• Epigenetic mapping: Detailed investigation of methylome changes following NNMT inhibition.

• Combination therapies: NNMT inhibitors with NAD⁺ precursors or epigenetic drugs.

References

1. Ulanovskaya OA, Zuhl AM, Cravatt BF. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol. 2013;9(5):300–306. PMID: 23503098

2. Kannt A, et al. Small-molecule NNMT inhibitors as research tools. Bioorg Med Chem Lett. 2018;28(14):2689–2693. DOI: 10.1016/j.bmcl.2018.06.027

3. Policarpo RL, et al. NNMT inhibition in adipose tissue ameliorates metabolic dysfunction. Cell Metab.2017;26(3):572–585. PMID: 28877456

4. Eckert MA, et al. NNMT expression contributes to tumorigenesis. Oncogene. 2019;38(9):1761–1775. PMID: 30374103

5. ClinicalTrials.gov. Search term: "NNMT inhibitor". Accessed September 2025.

⚠️ Disclaimer: This compound is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.