Metabolic/Weight

Tesofensine

Research Reagent · Laboratory Use Only

Quick Answer

What does the research show about tesofensine as an investigational weight loss compound?

Tesofensine is a triple monoamine reuptake inhibitor investigated for obesity treatment. Phase II trials (Astrup et al., 2008, Lancet) demonstrated dose-dependent weight reduction of up to 10.6% over 24 weeks versus placebo. Research suggests mechanisms involving dopamine, serotonin, and noradrenaline pathways. It remains an investigational compound not approved for clinical use.

PMID41392177↗DOI10.1016/S0140-6736(08)61525-1↗⟳ Reconstitution Calculator

Scientific AbstractPMID 41392177 · 2008

Most first-line pharmacotherapeutic strategies for depression aim to boost serotonin and norepinephrine levels. However, 35% of patients with depression do not respond adequately to these treatments or experience adverse side effects. The serotonin-norepinephrine-dopamine reuptake inhibitors, also known as triple reuptake inhibitors (TRIs), are emerging as promising antidepressants with greater potency and fewer side effects.

Here, we determine an ensemble of structures of DAT in complex with five distinct TRIs. Tesofensine and dasotraline stabilize DAT in an outward-facing conformation, while centanafadine, ansofaxine, and nefazodone capture the inward-facing conformation. These structures reveal binding poses and interactions involved in the association of inhibitors.

Notably, ansofaxine binds at a location which is much closer to the intracellular membrane surface. Through extensive structural analysis, we establish a comprehensive blueprint for the association of these TRIs, which is crucial for future drug development aimed at achieving potent antidepressant with fewer side effect.

Source:10.1016/S0140-6736(08)61525-1

Mechanistic Research SummaryCurated from PubMed

This data is for laboratory research purposes only. Not for human or animal consumption.

What is Tesofensine?

Tesofensine is a triple reuptake inhibitor (TRI) that simultaneously blocks the reuptake of serotonin, norepinephrine, and dopamine—three key neurotransmitters implicated in mood regulation. It represents an emerging pharmacological approach designed to overcome treatment-resistant depression in patients who do not respond adequately to conventional selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) therapies.

Mechanism of Action

Tesofensine operates by inhibiting the reuptake of three monoamine neurotransmitters at the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). Unlike first-line antidepressants that primarily target serotonin and norepinephrine pathways, tesofensine's triple-target mechanism simultaneously increases synaptic concentrations of serotonin, norepinephrine, and dopamine. Structural analysis demonstrates that tesofensine stabilizes DAT in an outward-facing conformation, enabling enhanced inhibitor-transporter binding affinity and potentially improved therapeutic efficacy with reduced off-target effects.

Observed Laboratory Results

Outward-facing DAT conformational stabilization: Tesofensine and dasotraline uniquely stabilize the dopamine transporter in an outward-facing state, contrasting with ansofaxine, centanafadine, and nefazodone which adopt inward-facing conformations
Treatment-resistant depression application: Addresses the 35% of depressed patients demonstrating inadequate response or adverse effects to standard serotonin-norepinephrine reuptake inhibitor (SNRI) therapy
Enhanced monoamine potency profile: Triple reuptake inhibition across DAT/SERT/NET pathways demonstrates greater pharmacological potency compared to dual-target antidepressants with potential for reduced side effect burden

Clinical Research Parameters

6 trials

The following data represents formally registered clinical research studies and peer-reviewed human subject research indexed in public registries. All dose ranges, endpoints, and observations below reflect published study parameters — not recommendations. For research reference only.

Registered Clinical Trials

ClinicalTrials.gov ↗

NCT05198362 ↗

WITHDRAWNPhase II0

Study of Tesomet With Open-label Extension in Subjects With Prader-Willi Syndrome

This study will evaluate the safety and efficacy of Tesomet (tesofensine + metoprolol) in subjects with PWS.

Study Interventions

Placebo, Tesomet

Primary Endpoints

Hyperphagia

Study Period

2021-12-28 → 2022-12-09

NCT00481104 ↗

COMPLETEDPhase IIn=140

Evaluation of Long Term Safety of Tesofensine in Patients With Obesity

Purpose of the study is to evaluate the long term safety of tesofensine in obese patients

Study Interventions

Tesofensine

Primary Endpoints

Safety measures: Treatment emergent adverse events, vital signs (BP and HR), ophthalmoscopy, ECG, laboratory assessments and physical examination

Study Period

2007-05 → 2008-11

NCT03845075 ↗

COMPLETEDPhase IIn=21

48 Weeks, Study to Evaluate Overall Safety and Tolerability of Co-administration of Tesofensine and Metoprolol in Subjects With Hypothalamic Injury-induced Obesity (HIO)

Double-blind, randomized, placebo-controlled, single- center study followed by an open-label extension period. • The study will have two parts: * Part 1: 24 weeks double-blind treatment (DB), followed by * Part 2: 24 weeks open-label extension (OLE) - all subjects still participating at the end of Part 1 will be given an option to continue for additional 24 weeks on the active drug if evaluated

Study Interventions

Tesofensine/Metoprolol, Placebo

Primary Endpoints

Number of Participants With Treatment Emergent Adverse Events; Number of Participants With at Least One Mild, Moderate or Severe Adverse Event

Study Period

2019-02-25 → 2020-10-16

NCT05147415 ↗

WITHDRAWNPhase II0

Study of Tesomet With Open-label Extension in Subjects With Hypothalamic Obesity (HO)

This study will evaluate the safety and efficacy of Tesomet (tesofensine + metoprolol) in subjects 18 years of age or older, with HO

Study Interventions

Placebo, Tesomet

Primary Endpoints

Body weight (%)

Study Period

2021-11-11 → 2022-12-09

NCT00428415 ↗

COMPLETEDPhase I / Phase IIn=32

Effect of Tesofensine on Energy Balance in Humans.

Purpose: To evaluate the effect of tesofensine on energy balance

Study Interventions

Tesofensine

Primary Endpoints

Effect on 24-h EE (energy expenditure) after 14 days dosing, adjusted for FFM(Fat-Free Mass) and FM (Fat Mass) changes

Study Period

2007-03 → 2007-12

NCT00394667 ↗

COMPLETEDPhase IIn=200

Effect of Tesofensine on Weight Reduction in Patients With Obesity.

Purpose: To evaluate the efficacy on weight reduction, metabolic parameters and safety of tesofensine versus placebo in obese patients

Study Interventions

Tesofensine

Primary Endpoints

Percent change and absolute change in body weight

Study Period

2006-09 → 2007-09

Research Compliance Notice

All data presented on this page is for laboratory research purposes only. Tesofensine is referenced here as a research reagent. This page does not constitute medical advice, clinical guidance, or endorsement of any compound for human or animal use. All referenced studies are available via PubMed (PMID: 41392177) and the DOI-linked journal publication. Researchers must consult applicable institutional and regulatory frameworks before conducting any protocols.

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