5-Amino 1MQ

5-Amino 1MQ (5-amino-1-methylquinolinium, CAS 42464-96-0) e um(a) sintetico(a) pequeno(a) molecule classificado(a) como a methylquinolinium derivative. [1] It foi desenvolvido(a) por Dr. Stanley J. Watowich’s grupo de pesquisa no(a) University of Texas Medical Branch (UTMB) at Galveston como um(a) selective inhibitor do(a) metabolic enzyme nicotinamide N-methyltransferase (NNMT). [2]

5-Amino 1MQ e um(a) analogue do(a) parent molecule 1-methylquinolinium (1-MQ), modified with a primary amine substitution no(a) 5-position do(a) quinoline ring. This structural modification was rationally projetado(a) para optimize afinidade de ligacao to NNMT enquanto dramatically improving membrane permeability — um(a) critico(a) limitation do(a) parent 1-MQ molecule. [3]

In conditions como obesidade, diabetes tipo 2, and aging, NNMT is overexpresso(a) em tecido adiposo and musculo esqueletico, onde it depletes cellular pools of NAD+ and SAM. By blocking NNMT, 5-Amino 1MQ preserva these critico(a) metabolic cofactors, shifting cellular metabolismo from fat storage to fat oxidation and energy expenditure. [4]

Regulatory Status:

• FDA: NOT registered for human use — experimental research chemical. [5]
• WADA: Banned under S0 category (Non-Approved Substances) — prohibited at all times.
• GRAS: Not classificado(a) como Generally Recognized as Well-tolerated for dietary supplementation.

Developer: Ridgeline Therapeutics (Houston, TX), founded by Dr. Watowich, is advancing a lead NNMT inhibitor candidate (RT-002) toward Phase 1 first-in-human ensaios clinicos, with IND-enabling GLP toxicology studies in minipigs atualmente underway. [6]

Pharmacokinetic Highlights:

• Oral Bioavailability: 38.4% (rats) [7]
• Half-Life: ~6.9 hours (oral), ~3.8 hours (IV) in rats
• Cmax: 2,252 ng/mL (oral, rats)
• Membrane Permeability: High (passive and ativo(a) transport)

1. Primary Target — NNMT Enzyme

The molecular target of 5-Amino 1MQ e o(a) cytosolic enzyme nicotinamide N-methyltransferase (NNMT), a metabolic regulator highly expresso(a) em tecido adiposo, liver, and musculo esqueletico — particularmente in obesidade and diabetes tipo 2. [2]

Binding Mechanism: 5-Amino 1MQ is a substrate-competitive inhibitor. It competes with nicotinamide (NAM) para o(a) ativo(a) binding site of NNMT, preventing a enzima from catalyzing the transfer of a methyl group from SAM to NAM. This blockade previne formation of 1-methylnicotinamide (1-MNA) and S-adenosyl-L-homocysteine (SAH). [3]

Potency:

• IC₅₀: ~1.0–1.2 µM for NNMT inibicao [1]
• EC₅₀: 2.3 ± 1.1 µM (reduction of intracellular 1-MNA levels) [1]
• Lipogenesis Inhibition: 30 µM reduziu lipogenesis by 50%; 60 µM by 70%

2. Downstream Cascade A — NAD+ Salvage and SIRT1 Activation

NNMT normally acts como um(a) “sink” for nicotinamide, permanently removing it do(a) NAD+ salvage pathway by methylating it into 1-MNA (which is then excreted). By inhibiting NNMT, 5-Amino 1MQ preserva the intracellular NAM pool, shunting it back no(a) NAD+ salvage pathway and significantly increasing intracellular NAD+ levels. [4]

Elevated NAD+ acts como um(a) co-substrate for sirtuins, specifically activating SIRT1 — often called the “longevity gene.” SIRT1 ativacao drives aumentou biogenese mitocondrial and metabolic rate. [8]

3. Downstream Cascade B — Methionine-SAM Cycle and Epigenetic Regulation

NNMT consumes SAM (the universal methyl donor) during NAM metilacao. 5-Amino 1MQ previne this consumption, increasing intracellular SAM levels and reducing SAH (a metilacao inhibitor). This alters the cell’s epigenetic metilacao potential, influencing histone and DNA metilacao states que regulate expressao genica for adipogenesis and metabolismo. [4] [9]

4. Downstream Cascade C — Exercise Mimicry (Muscle-Specific)

In musculo esqueletico, 5-Amino 1MQ desencadeia unique signaling: [10]

• Ribosomal Biogenesis: Upregula proteins envolveu in ribosomal RNA biogenesis and aminoacyl-tRNA ligase activity, mimicking a proteina traducao signaling normally induzido(a) por exercise.
• Transsulfuration Pathway: Unicamente upregula the transsulfuration pathway (via cystathionine β-synthase), enhancing protection against reactive oxygen species (ROS) via glutathione synthesis.
• AMPK Activation: Shifts the metabolome of sedentary muscle toward an exercised state via aumentou AMP, driving AMPK ativacao — um(a) critico(a) energy sensor promoting muscle hypertrophy and protein traducao.

5. Receptor Selectivity

5-Amino 1MQ demonstra high selectivity for NNMT, avoiding off-target effects: [3]

• Does NOT inhibit structurally related SAM-dependent methyltransferases: DNMT1, PRMT3, COMT
• Does NOT inhibit NAD+ pathway enzymes: NAMPT, SIRT1

This confirma que NAD+ and SAM aumenta result solely from preventing their degradacao by NNMT, not from interfering with their synthesis or utilization enzymes.

6. Cellular and Tissue-Level Effects

Adipose Tissue (White Fat):

• Suppresses lipogenesis (fat creation) in adipocitos [1]
• Reduces white adipocito size by >30% and WAT mass by ~35% [2]
• Produces um(a) unico(a) metabolomic signature (aumentou ketogenic aminoacidos)
• No alteration in food intake [2]

Skeletal Muscle:

• Activates senescent muscle celulas-tronco (MuSCs), promoting proliferacao and myofiber repair [11]
• Nearly 2-fold increase in myofiber cross-sectional area; ~70% increase in peak torque
• Sustained running capacity sem fatigue taper [10]

Liver:

• Reverses hepatico(a) steatosis (fatty liver) and normalizes ALT/AST [12]
• Reduces total plasma cholesterol by ~30% [2]

7. Pharmacokinetics

Source: Awosemo/Neelakantan et al., J. Pharm. Biomed. Anal., 2021 [7]

🏋️ Obesity & Fat Loss

In diet-induziu obese (DIO) mice, 5-Amino 1MQ (20 mg/kg SC, 3× daily, 11 days) reduziu peso corporal by 5.1%, diminuiu epididymal white tecido adiposo (WAT) mass by ~35% (P<0.001), and reduziu adipocito size by >30%, all sem altering food intake. Plasma total cholesterol diminuiu ~30% (P<0.05). [2] In a longer study (32 mg/kg daily, 7 weeks), massa gorda diminuiu by 29.3%, normalizing composicao corporal to levels indistinguishable from age-matched lean controls. [9]

Veja tambem: AOD-9604 para pesquisas relacionadas sobre fat metabolismo research.

💊 Type 2 Diabetes & Metabolic Syndrome

5-Amino 1MQ melhorou oral glucose tolerance and suprimiu hyperinsulinemia in obese modelo de camundongos. It addresses the underlying metabolic dysfunction in white tecido adiposo que drives resistencia a insulina. [12]

Veja tambem: Tirzepatide para pesquisas relacionadas sobre metabolic research.

💪 Muscle Regeneration & Sarcopenia

In aged (22-month) mice, 5-Amino 1MQ (10 mg/kg daily, 8 weeks) mimicked exercise effects: sedentary treated mice showed ~40% greater grip strength do que untreated controls (P<0.001). Combined with exercise, grip strength aumentou by ~60%. Treated mice manteve a 1.8 km/day running increase na semana 8, enquanto untreated mice tapered off (P=0.0039). Intramyocellular lipid content diminuiu >30%. [10]

In aged (24-month) mice with agudo(a) muscle injury, treated animals showed nearly 2× greater myofiber cross-sectional area and ~70% aumentou peak torque (P<0.05), with aprimorou muscle stem cell (MuSC) proliferacao and fusion. [11]

🫁 Doenca Hepatica (NAFLD/NASH)

Combined diet switch + 5-Amino 1MQ aplicacao em pesquisa (28 days) normalized ALT and AST liver enzyme levels, reduziu liver weight/size and triglyceride content, atenuou hepatico(a) steatosis and macrofago infiltration. [12]

🧬 Duchenne Muscular Dystrophy (DMD)

Estudos pre-clinicos indicate que NNMT inibicao can improve muscle regeneration and function in DMD models by enhancing mitochondrial bioenergetics and reactivating dysfunctional muscle celulas-tronco. [11]

🪸 Chronic Kidney Disease (CKD)

Research targeting NNMT inibicao shows potential in reducing renal fibrose and tubular senescencia, with melhorou kidney function and slowed progressao da doenca in CKD models. [13]

🎯 Cancer (NNMT Overexpression)

NNMT is overexpresso(a) em aggressive cancers incluindo glioblastoma, ovarian cancer, and gastric cancer, driving metabolic and epigenetic remodeling que apoia tumor growth. 5-Amino 1MQ is being investigated for its potential para suprimir tumorigenesis, metastasis, and chemoresistance. [14]

⏳ Longevity & Anti-Aging

By elevating intracellular NAD+ levels and activating SIRT1, 5-Amino 1MQ is explored como um(a) experimental para retardar cellular aging, improve mitochondrial health, and prevent age-related physiological decline. [8]

Preclinical Animal Studies

• Obesity — DIO Mice (Neelakantan 2018): 20 mg/kg SC 3×/day, 11 days. -5.1% peso corporal (P<0.0001 at day 10), -35% WAT mass (P<0.001), >30% diminuiu adipocito size and >40% diminuiu volume (P<0.05), ~30% lower plasma cholesterol (P<0.05). No change in food intake; no adverse toxicity. [2]
• Obesity + Diet (Sampson 2021): 32 mg/kg SC daily, ~7 weeks (DIO mice switched to lean diet). -29.3% massa gorda em relacao ao basal vs. -2.9% for diet alone. Body composition normalized to lean controls. Metabolomic analysis predicted lipid synthesis inibicao (z-score = -2.566, P=0.045). [9]
• Microbiome (Dimet-Wiley 2022): 32 mg/kg SC daily, ~7 weeks. Treated mice showed distinct microbiome cluster with aumentou Lactobacillus and Parasutterella; diminuiu Erysipelatoclostridium. [15]
• Metabolic/Liver (Babula 2024): Daily SC, 28 days (DIO mice). Normalized ALT/AST, melhorou oral glucose tolerance, suprimiu hyperinsulinemia, reduziu liver weight and triglycerides, atenuou steatosis and macrofago infiltration. [12]
• Exercise Mimicry (Dimet-Wiley 2024): 10 mg/kg SC daily, 8 weeks (aged 22-month mice). Sedentary treated: +40% grip strength (P<0.001). Exercise + treated: +60% grip strength, manteve 1.8 km/day running increase na semana 8 (P=0.0039). >30% reduction in intramyocellular lipid. [10]
• Muscle Regeneration (Neelakantan 2019): 5–10 mg/kg, 1–3 weeks (aged 24-month mice with agudo(a) injury). ~2× myofiber CSA, +70% peak torque (P<0.05), aumentou MuSC proliferacao and fusion. [11]
• Peripheral Artery Disease (Dong 2025): Daily dosing (BALB/cJ mice with hindlimb isquemia). Significantly melhorou muscle strength (P<0.0001), power (P=0.031), total work (P=0.037). Independent of perfusao or capillary changes. [16]

Pharmacokinetic Profile (Rats)

Awosemo/Neelakantan et al. (2021): Oral biodisponibilidade 38.4%; T½ 6.9h (oral) / 3.8h (IV); Cmax 2,252 ng/mL. High membrane permeability. No 24-hour accumulation in heart, liver, kidney, or brain (recirculation observado(a) at ~12h). Cross-species liver metabolic stability confirmou. [7]

relatado(a) perfil de tolerabilidade (Preclinical)

Acute Toxicity: In mice, animals survived doses from 50 mg/kg to 2,000–5,000 mg/kg with no observable adverse reactions during 48-hour monitoring. [2]

Subacute Toxicity (14 days): Liver (AST, GGT), heart (troponin I), and inflammatory (CRP) markers were unaffected except for significant CRP rise at highest IV dose (200 mg/kg) at 6 hours post-dose. [2]

Cell Viability: No impact up to 100 µM; modest cytotoxicity at 100–300 µM; ~40% cytotoxicity at 600 µM in 3T3-L1 adipocitos. [1]

Clinical Development Status

Ridgeline Therapeutics (founded by Dr. Watowich) is developing a lead NNMT inhibitor candidate (RT-002), conducting IND-enabling GLP toxicology studies in minipigs com o(a) goal of submitting an IND briefing package para o(a) FDA for Phase 1 first-in-human ensaios clinicos. [6]