SLU-PP-332 vs 5-Amino-1MQ comes up a lot, mostly because both get filed under “metabolic research” and both are small molecules, not peptides. That’s where the similarity ends. SLU-PP-332 turns on ERR nuclear receptors and pushes cells toward burning fat. 5-Amino-1MQ blocks an enzyme, NNMT, that quietly eats into the cell’s NAD+ supply. Fair warning: a lot of older content online (including an earlier version of this page) mixed SLU-PP-332 up with REV-ERB agonists. It isn’t one. Here’s what the primary papers actually show.
Key findings
- SLU-PP-332 is a pan-ERR agonist (ERRα, β, γ) with its highest potency at ERRα, not a REV-ERB agonist (Billon 2023).
- In obese mice, SLU-PP-332 raised energy expenditure and fatty acid oxidation and reduced fat mass (Billon 2024).
- 5-Amino-1MQ belongs to a methylquinolinium series of NNMT inhibitors that raised intracellular NAD+ and SAM in adipocytes (Neelakantan 2018).
- In diet-induced obese mice, an NNMT inhibitor from that series reduced body weight and white fat without changing food intake.
- In 24-month-old mice, NNMT inhibition after muscle injury raised peak torque by about 70% versus controls (Neelakantan 2019).
- There’s no human data for either compound and no head-to-head study.
Two different targets
Start with SLU-PP-332. It was designed by Burris, Walker and colleagues to activate the estrogen-related receptors, a trio of orphan nuclear receptors that control mitochondrial and fat-oxidation genes. Despite the name, ERRs don’t bind estrogen. SLU-PP-332 hits all three, leans toward ERRα, and has pharmacokinetics good enough for mouse work [1].
5-Amino-1MQ (5-amino-1-methylquinolinium) is an enzyme inhibitor. Its target, nicotinamide N-methyltransferase, takes nicotinamide (a form of vitamin B3) and slaps a methyl group on it using SAM. That uses up a precursor the cell would otherwise turn into NAD+, and burns SAM too. Block NNMT and, in principle, you keep more of both.
Why would anyone care? Because of a 2014 Nature paper from Barbara Kahn’s lab. They found NNMT expression went up in fat and liver of obese, diabetic mice, and knocking it down in those tissues protected mice from diet-induced obesity by raising energy expenditure [2]. That paper basically put NNMT on the map as a metabolic target.
| SLU-PP-332 | 5-Amino-1MQ | |
|---|---|---|
| Class | Synthetic ERR agonist | Methylquinolinium NNMT inhibitor |
| What it does | Activates receptors that drive mitochondrial genes | Blocks an enzyme that consumes nicotinamide and SAM |
| Main readouts in papers | Endurance, fiber type, energy expenditure, fat mass | NAD+, SAM, fat mass, muscle stem cell activity |
| Human studies | None published | None published |
What SLU-PP-332 did in mice
The 2023 ACS Chemical Biology study showed SLU-PP-332 boosting mitochondrial function and cellular respiration in a muscle cell line. In mice it increased type IIa oxidative fibers and improved endurance. When ERRα was removed, the endurance effect disappeared, which is a nice on-target check [1].
The 2024 follow-up went after obesity. In diet-induced obese and ob/ob mice, SLU-PP-332 raised energy expenditure and fatty acid oxidation, cut fat mass accumulation and improved insulin sensitivity [3].
A separate Circulation paper tested it in a mouse model of pressure overload heart failure. Ejection fraction improved, fibrosis dropped and survival went up, and that heart effect ran mostly through ERRγ [4].
What 5-Amino-1MQ and its relatives did
Most of the NNMT inhibitor work comes from Stanley Watowich’s group at UTMB in Galveston. Their 2018 paper looked at a series of methylquinolinium compounds with primary amine substitutions, which is the family 5-Amino-1MQ belongs to. These crossed membranes well, didn’t inhibit related methyltransferases or NAD+ salvage enzymes, and in cultured fat cells they lowered 1-MNA (the NNMT product), raised NAD+ and SAM, and suppressed lipogenesis [5].
In diet-induced obese mice on a high-fat diet, a potent inhibitor from that series reduced body weight and white fat mass, shrank fat cells and lowered total cholesterol. Food intake didn’t change, and the authors saw no observable adverse effects [5]. That’s the part people latch onto: weight came off without the mice eating less.
A 2021 study paired NNMT inhibition with a switch to a lean diet. Compared with the diet switch alone, the combination sped up fat loss, raised the lean mass to body weight ratio and improved fatty liver, bringing body composition back to lean control levels [6].
Then there’s muscle. In 24-month-old mice with a chemically induced muscle injury, NNMT inhibition raised muscle stem cell proliferation and fusion, gave nearly 2-fold larger fiber cross-sectional area, and lifted peak torque by roughly 70% compared to controls [7]. That’s a big effect for an old mouse.
One small aside: a 2021 cell study also tested 5-Amino-1MQ on HeLa cervical cancer cells and saw reduced proliferation [8]. It’s a single in vitro paper, so read it as a lead, not a finding.
Where they overlap, and where they don’t
Both compounds end up in the same neighborhood: more energy expenditure, less fat, better mitochondrial behavior in mice. But the roads are different. SLU-PP-332 flips a transcriptional switch. 5-Amino-1MQ changes the supply of two metabolites (NAD+ and SAM) that feed into lots of pathways, including sirtuin signaling and histone methylation.
That matters for study design. If you’re asking about ERR target genes or fiber-type shifts, SLU-PP-332 is the cleaner tool. If your question is about NAD+ metabolism, methylation balance or aged muscle repair, 5-Amino-1MQ fits better. Could they be studied together? Mechanistically it’s an interesting idea, but nobody’s published that, and we won’t pretend otherwise.
Also worth saying plainly: both literatures are small and come mostly from a single group each, with company ties disclosed in some papers. Independent replication would help a lot.
For more detail, see our SLU-PP-332 compound profile and the 5-Amino-1MQ compound profile.
References
- Billon C, Sitaula S, Banerjee S, et al. Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity. ACS Chem Biol. 2023. PMID: 36988910
- Kraus D, Yang Q, Kong D, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014. PMID: 24717514
- Billon C, Schoepke E, Avdagic A, et al. A Synthetic ERR Agonist Alleviates Metabolic Syndrome. J Pharmacol Exp Ther. 2024. PMID: 37739806
- Xu W, Billon C, Li H, et al. Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function. Circulation. 2024. PMID: 37961903
- 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. Biochem Pharmacol. 2018. PMID: 29155147
- Sampson CM, Dimet AL, Neelakantan H, et al. Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition and enhances metabolic benefits in obese mice. Sci Rep. 2021. PMID: 33707534
- Neelakantan H, Brightwell CR, Graber TG, et al. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochem Pharmacol. 2019. PMID: 30753815
- Akar S, Duran T, Azzawri AA, et al. Small molecule inhibitor of nicotinamide N-methyltransferase shows anti-proliferative activity in HeLa cells. J Obstet Gynaecol. 2021. PMID: 33645410
Disclaimer: This content is intended for research purposes only and is not meant to constitute medical advice.
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