5-Amino-1MQ

5-Amino-1MQ (5-amino-1-methylquinolinium) is a small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT), an enzyme that plays a critical role in cellular energy metabolism and NAD+ regulation. By inhibiting NNMT, 5-Amino-1MQ increases intracellular NAD+ levels and S-adenosylmethionine (SAM) availability, leading to enhanced energy expenditure, reduced fat accumulation, and improved metabolic function in preclinical models. This compound has demonstrated significant potential for treating obesity, metabolic syndrome, and age-related muscle decline in animal studies, though no human clinical trials have been published to date.

Metabolic and Weight Loss Benefits

Fat Loss and Body Composition: 5-Amino-1MQ treatment has demonstrated remarkable effects on body composition in preclinical studies. In diet-induced obese mice, 11-day treatment with 5-amino-1MQ produced approximately 5.1% body weight loss versus 1.4% gain in controls, with ~35% reduction in epididymal white adipose tissue mass and >30% decrease in adipocyte size^[1]. The compound dose-dependently limited body weight and fat mass gains, with treated mice showing significantly reduced body weights, white adipose masses, and adipocyte sizes compared to untreated controls^[2][3]. When combined with reduced-calorie diet, 5-Amino-1MQ accelerated body weight and fat loss beyond diet alone, normalizing body composition to age-matched lean control levels and increasing the lean-to-body-weight ratio by 6.4%^[4].

Enhanced Energy Expenditure: The mechanism underlying these effects involves increased cellular energy expenditure without appetite suppression. Studies consistently show that 5-Amino-1MQ treatment did not significantly impact food intake, indicating weight loss resulted from genuinely altered metabolism rather than reduced caloric consumption^[1][2]. By inhibiting NNMT, the compound increases intracellular NAD+ concentrations, which activates NAD+-dependent enzymes like SIRT1 that enhance mitochondrial function and promote increased energy expenditure^[5][6].

Improved Glucose Metabolism and Insulin Sensitivity: 5-Amino-1MQ treatment improved oral glucose tolerance and insulin sensitivity while suppressing hyperinsulinemia in diet-induced obese mice^[2]. NNMT knockdown studies have shown significant improvements in fasting blood glucose levels and normalization of glucose tolerance, demonstrating the therapeutic potential for type 2 diabetes management^[6][7].

Liver Health and Reduced Hepatic Steatosis: Treatment with 5-Amino-1MQ produced significant improvements in liver health, with histological analysis showing attenuated hepatic steatosis (fatty liver), reduced macrophage infiltration, and correspondingly reduced liver weight in treated mice^[2]. Combined NNMT inhibition and reduced-calorie diet restored fatty liver profiles in previously obese animals to levels observed in lean controls, reducing both microvesicular and macrovesicular steatosis scores^[4].

Muscle Function and Anti-Aging Benefits

Enhanced Muscle Strength and Function: NNMT inhibition has demonstrated remarkable effects on muscle function, particularly in aging. Treatment with 5-Amino-1MQ in aged mice (22-24 months) showed ~40% greater grip strength compared to sedentary controls, significantly outperforming exercise alone which only produced 20% improvement^[8]. When combined with exercise, the effects were additive, yielding 60% grip strength gains relative to sedentary controls^[8].

Improved Muscle Regeneration: In aged skeletal muscle, NNMT inhibitors activate senescent muscle stem cells and improve regenerative capacity. Treatment of 24-month-old mice with NNMT inhibitors following acute muscle injury resulted in nearly 2-fold greater cross-sectional area of regenerating myofibers and approximately 70% improvement in peak contractile force compared to controls^[9]. Muscle stem cell proliferation and subsequent fusion were elevated in treated animals, supporting enhanced tissue repair^[9].

Protection Against Sarcopenia: Studies have identified NNMT as a promising therapeutic target for sarcopenia, the age-related loss of muscle mass and strength. NNMT inhibitor treatment attenuated the decrease in grip strength and improved muscle mass indices in aging models, suggesting potential therapeutic applications for maintaining muscle health in older adults^[10].

Cellular and Metabolic Mechanisms

NAD+ Restoration: 5-Amino-1MQ significantly increases intracellular NAD+ levels by preventing nicotinamide methylation, thereby preserving NAD+ precursor availability. This is particularly important because NAD+ is a critical coenzyme in mitochondrial energy metabolism and declines with age and obesity^[5][6][11].

Suppressed Lipogenesis: In vitro studies with adipocytes demonstrate that 5-Amino-1MQ significantly reduces intracellular 1-methylnicotinamide (MNA), increases SAM levels, and suppresses lipogenesis (fat synthesis and storage) with an EC50 of 30 μM^[1][5].

Epigenetic Benefits: NNMT inhibition affects cellular methylation balance through increased SAM availability, which influences histone methylation and gene expression patterns. This epigenetic regulation plays a role in metabolic improvements and cellular function restoration^[6][11][12].

Microbiome Modulation: Combined treatment with 5-Amino-1MQ and reduced-calorie diet established a distinct gut microbiome profile in obese mice, with decreased Erysipelatoclostridium and increased Lactobacillus relative abundances—bacterial genera linked to improved metabolic regulation^[3].

Preclinical Safety Profile

Lack of Observable Adverse Effects: In multiple animal studies, 5-Amino-1MQ treatment did not produce observable adverse effects during experimental periods. Mice treated with the compound at therapeutic doses (ranging from 5-34 mg/kg/day) showed no signs of toxicity, behavioral changes, or general health deterioration^[1][2][8]. Notably, the weight loss and metabolic improvements occurred without appetite suppression or signs of illness, suggesting the effects result from targeted metabolic modulation rather than general malaise^[1].

Cellular Viability: In vitro studies demonstrated that treatment of cells with 10 μM 5-amino-1MQ for 24 hours did not impact cell viability, indicating good tolerability at therapeutically relevant concentrations^[1]. However, at very high concentrations (500 μM), the compound showed anti-proliferative effects in cancer cell lines, which may represent either a therapeutic benefit or a safety concern depending on concentration and context^[13].

Selectivity Profile: 5-Amino-1MQ demonstrates high selectivity for NNMT and does not inhibit related SAM-dependent methyltransferases or enzymes in NAD+ salvage pathways, reducing the risk of off-target effects^[1][5]. This selectivity is important for minimizing unintended metabolic disruptions.

Pharmacokinetic Profile: In rat studies, 5-Amino-1MQ displayed moderate oral bioavailability (38.4%), with peak plasma concentrations of 2,252 ng/mL after oral dosing and elimination half-lives of 3.80 ± 1.10 hours (IV) and 6.90 ± 1.20 hours (oral)^[11]. The compound demonstrated stability in plasma samples under standard storage and handling conditions^[11]. The compound achieved effective tissue penetration in metabolically active organs including adipose tissue, skeletal muscle, and liver^[2].

Important Safety Limitations and Concerns

Absence of Human Clinical Data: The most significant safety limitation is the complete absence of published human clinical trials. All current safety and efficacy data come exclusively from preclinical research in cells and animal models^[5][6]. The lack of human data means that safety, appropriate dosing, drug interactions, and potential side effects in humans remain unknown.

No Long-Term Safety Data: Even in animal models, most studies have been relatively short-term (typically 11-28 days for obesity studies, though muscle studies extended to several weeks). Long-term safety, potential for tolerance development, and effects of chronic administration have not been adequately characterized^[1][2][4].

Regulatory Status: 5-Amino-1MQ has not been approved by the FDA or any other regulatory agency for medical use. It is currently sold only as a research chemical, and its use in humans outside of formal clinical trials is not supported by regulatory authorities.

Potential Concerns with NNMT Inhibition: While NNMT inhibition shows benefits in adipose tissue and muscle, the enzyme demonstrates tissue-specific functions. In hepatic tissue, NNMT may provide beneficial metabolic effects, and its role can vary by tissue type and physiological context^[12]. The long-term consequences of systemic NNMT inhibition across all tissues require further investigation.

Cancer Cell Effects: While 5-Amino-1MQ showed anti-proliferative activity in cancer cells (HeLa cells), which could theoretically be beneficial, it also affected various oncogenic pathways in complex ways^[13]. The implications of these effects for cancer risk or progression in non-cancerous contexts remain unclear.

Bioavailability Inconsistencies: There are conflicting findings regarding oral bioavailability, with some studies showing moderate bioavailability (38.4% in rats)^[11] while others suggest poor oral bioavailability in mice requiring subcutaneous injection. This inconsistency highlights species differences and the need for human pharmacokinetic studies.

Quality and Purity Concerns: As an unregulated research chemical, 5-Amino-1MQ products available commercially may vary in purity, contain contaminants, or be mislabeled. Without pharmaceutical-grade manufacturing standards, product quality cannot be guaranteed.

Recommendations

Medical Supervision Required: Given the experimental nature of this compound and the absence of human safety data, any use should only occur under medical supervision within the context of properly designed clinical trials.

Contraindications Unknown: Without human studies, appropriate contraindications, drug interactions, and special population considerations (pregnancy, lactation, pediatric use, hepatic/renal impairment) have not been established.

Need for Clinical Trials: Rigorous human clinical trials are essential to establish safety profiles, determine appropriate dosing, identify potential adverse effects, and confirm that the metabolic benefits observed in animal models translate to humans^[6].