Tesofensine
| Category | Compounds |
|---|---|
| Also known as | NS2330 |
| Last updated | 2026-04-14 |
| Reading time | 3 min read |
| Tags | metabolicmonoamine-reuptake-inhibitorweight-losscnsresearch |
Overview
Tesofensine is a small-molecule triple monoamine reuptake inhibitor that blocks the presynaptic reuptake of dopamine, norepinephrine, and serotonin. Originally developed as a candidate for Parkinson's and Alzheimer's disease, the program pivoted after investigators observed unexpectedly strong weight loss in early trials.
Subsequent phase II studies in obesity reported dose-dependent reductions in body weight that in some comparisons exceeded those observed with other weight-management drugs available at the time. Cardiovascular and psychiatric signal monitoring slowed its path in Western regulatory systems, but it has since reached approval for obesity in Mexico and remains an active research compound elsewhere. It is commonly cross-referenced with peptide-based agents like Semaglutide, Cagrilintide, and Setmelanotide.
Although tesofensine is a small molecule rather than a peptide, it is widely discussed in peptide and metabolic research communities because of its unusually strong effect on appetite and energy expenditure. That puts it in conceptual company with agents like Adipotide and 5-Amino-1MQ.
Structure / Chemistry
Tesofensine is a tropane-derived small molecule (molecular weight roughly 346 g/mol in its base form) structurally related to early-generation dopamine reuptake inhibitors. It is administered orally and is not a peptide, though it is catalogued in peptide research databases due to its metabolic profile.
Mechanism of Action
Tesofensine inhibits reuptake of dopamine, norepinephrine, and serotonin in the central nervous system. The resulting elevations in synaptic monoamines are thought to act on hypothalamic and reward-circuit pathways that regulate appetite and satiety, overlapping mechanistically with melanocortin signaling studied for drugs like Setmelanotide.
Research Summary
| Area | Finding | Reference |
|---|---|---|
| Phase II obesity | Dose-dependent weight loss up to ~11% over 24 weeks | Astrup et al., Lancet 2008 |
| Pharmacology | Triple monoamine reuptake inhibition characterized | Lehr et al., Eur J Pharmacol 2008 |
| Mechanism | Appetite suppression via hypothalamic monoamine tone | Axel et al., Int J Obes 2010 |
| Cardiovascular | Heart rate and BP signal observed at higher doses | Astrup et al., Lancet 2008 |
| Real-world | Post-approval Mexican cohort outcomes | Multiple observational reports |
Pharmacokinetics
Tesofensine is orally bioavailable with a long plasma half-life (reported around 8-9 days in humans), allowing once-daily dosing. Steady state is reached after several weeks. Typical doses in clinical trials ranged from 0.25 to 1.0 mg daily. Dosing information here is reference only and not medical guidance.
Common Discussion Topics
- Comparison with GLP-1 and amylin peptides like Semaglutide and Cagrilintide.
- Cardiovascular and psychiatric monitoring considerations.
- Long half-life and dose titration implications.
- Regulatory status differences across jurisdictions.
- Potential for combination research with melanocortin agents.
Related Compounds
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Related entries
- 5-Amino-1MQ— 5-Amino-1MQ is a small-molecule NNMT inhibitor studied for its effects on adipose metabolism, NAD+ preservation, and methylation balance.
- Adipotide— Adipotide is a proapoptotic peptide designed to target adipose-tissue vasculature, studied in preclinical obesity models for adipose-specific fat reduction.
- Cagrilintide— Cagrilintide is a long-acting amylin analog investigated for weight management, often studied in combination with GLP-1 receptor agonists.
- Semaglutide— A long-acting GLP-1 receptor agonist approved for type 2 diabetes (Ozempic) and chronic weight management (Wegovy), with emerging cardiovascular, renal, and neurological research applications.
- Setmelanotide— A synthetic cyclic octapeptide melanocortin 4 receptor agonist, setmelanotide is an FDA-approved treatment for chronic weight management in patients with obesity due to specific monogenic defects in the leptin-melanocortin signaling pathway, including POMC, PCSK1, and LEPR deficiency.