Everything below reports findings from cell cultures, isolated tissue and animals. This material is for research use only, not for human or veterinary use.
Two facts about tesofensine matter more than anything else for anyone designing an experiment with it, and neither appears in most summaries.
The first is kinetic. Population modelling in 320 patients measured two terminal half-lives. Parent compound came in at 234 hours, its major metabolite at 374 hours [8]. That is roughly ten days and fifteen days. Steady state takes weeks to reach, and washout takes months.
The second is that the compound is never present alone. A metabolite designated M1 accumulates to roughly eightfold higher steady-state concentrations than parent, and it carries its own activity [7].
Together those facts have one consequence. Any study using Tesofensine observes a two-species mixture whose ratio shifts with time, at concentrations still climbing long after dosing begins.
Indexed human papers exist. Those human doses, human pharmacodynamic endpoints and human obesity-trial outcomes are outside the scope of this profile. The laboratory questions are chemistry, transporter logic, and what rodent systems actually measured.
Chemical identity: what you are actually handling
Tesofensine is a tropane derivative, sharing its bicyclic core with a large family of transporter ligands.
| Property | Value |
|---|---|
| IUPAC name | (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane |
| Synonym | NS 2330 |
| CAS | 195875-84-4 |
| Molecular formula | C17H23Cl2NO |
| Molecular weight | 328.28 g/mol |
| PubChem CID | 11370864 |
| InChIKey | VCVWXKKWDOJNIT-ZOMKSWQUSA-N |
| Stereocentres | Four, defined |
| Halogens | Two chlorines, aromatic |
| Originator | NeuroSearch |
The tropane scaffold
The core is an 8-azabicyclo[3.2.1]octane, the same framework found in cocaine and in the transporter radioligands used for dopamine imaging. Here it carries a 3,4-dichlorophenyl group at position 3 and an ethoxymethyl group at position 2.
Sharing a tropane scaffold invites an inference that the pharmacology does not support. Scaffold resemblance is not a binding assay. It is not an identity check either.
Tesofensine is a lipophilic tertiary amine carrying an ether linkage and no ester. That ether resists hydrolysis. Basicity comes from the amine, so the compound forms salts with acids and its aqueous solubility depends on pH.
Four stereocentres and no chiral shortcut
The compound carries four stereocentres in the (1R,2R,3S,5S) configuration. Several stereoisomers share its molecular formula and accurate mass exactly.
That makes chiral chromatography a requirement rather than a refinement. A certificate reporting purity by a standard reversed-phase method has not established that the material matches the compound in the published literature.
PubChem CID 11370864 and InChIKey VCVWXKKWDOJNIT-ZOMKSWQUSA-N close the record. A lot that fails those checks is not Tesofensine, whatever the label says.
Tesofensine transporter pharmacology
Tesofensine blocks reuptake at all three monoamine transporters, inhibiting dopamine, noradrenaline and serotonin transport [1].
Triple inhibition distinguishes it from the selective agents that dominate this space. Blocking one transporter produces a comparatively narrow neurochemical change. Blocking three raises synaptic availability across three systems at once. No single-transporter comparator predicts that combined profile.
In-vitro potencies
Appel and colleagues restated the synaptosome potencies that sit behind the imaging paper (PMID 24239329) [10]. Rat-brain synaptosome IC50 values were 6.5 nM at the dopamine transporter, 1.7 nM at the noradrenaline transporter and 11 nM at the serotonin transporter.
Lehr and colleagues reported the same order for parent and a tighter set for M1 [7]. M1 IC50 values were 3.0 nM at dopamine, 0.6 nM at noradrenaline and 2.0 nM at serotonin. The metabolite is the more potent species on those numbers. It is also the species that accumulates.
| Species | DAT IC50 | NET IC50 | SERT IC50 | Source |
|---|---|---|---|---|
| Tesofensine | 6.5 nM | 1.7 nM | 11 nM | Rat synaptosomes [10] |
| M1 (NS2360) | 3.0 nM | 0.6 nM | 2.0 nM | Lehr 2008 [7] |
Treat those figures as a rank order, not as a certificate for an unknown vial. A lot that fails chiral identity is not the compound those tables describe.
The receptor pathways behind the feeding effect
Transport blockade is upstream. Which receptors carry the downstream signal is a separate question, and one study answered it by systematic antagonism.
Axel and colleagues treated diet-induced obese rats and measured food intake across twelve hours, then tested which receptor antagonists blocked the effect [2].
The result was specific. Prazosin, an alpha1 adrenoceptor antagonist, almost completely reversed the hypophagic response. SCH23390, a dopamine D1 antagonist, partially antagonised it. Four other antagonists did nothing at all. Those were an alpha2 antagonist, a D2 antagonist, a D3 antagonist, and a 5-HT2A/C antagonist [2].
That pattern narrows a broad mechanism to two pathways. The compound blocks serotonin transport, yet the feeding effect in this model ran through alpha1 adrenoceptor and D1 receptor function instead [2].
The half-maximal effective dose for the hypophagic response was 1.3 mg/kg subcutaneously in that model [2].
Receptor pathways in diet-induced obese rats
Most research compounds have no circuit-level work behind a feeding readout. Tesofensine has several rodent papers, and they do not all point the same way.
Accumbal dopamine and D2/D3 availability
Hansen and colleagues found diet-induced obese rats had reduced baseline extracellular dopamine in nucleus accumbens and prefrontal cortex compared with chow-fed animals. Acute tesofensine normalised accumbal dopamine in obese rats while having no effect in chow-fed rats [4].
Van de Giessen and colleagues measured striatal dopamine D2/D3 receptor availability after 28 days of treatment. It came out lower in treated animals than in either vehicle controls or calorie-restricted controls. No correlation appeared between food intake or body weight and receptor availability. The authors therefore described the receptor change as mainly a pharmacological effect rather than a mediator of the weight change [5]. Caloric intake and weight gain returned after treatment stopped [5].
Lateral hypothalamic ensembles
A 2024 study took the mechanism to the circuit level, recording neuronal ensembles in the lateral hypothalamus and using optogenetic and chemogenetic tools in transgenic mice (PMID 38656972) [6].
Tesofensine inhibited a subset of GABAergic lateral hypothalamic neurons, reducing their capacity to promote feeding. Chemogenetic silencing of those same neurons enhanced the food-suppressing effect [6]. The study also reported that effects on sucrose responses were independent of taste aversion and did not alter perception of sweetness or palatability [6].
One comparative observation belongs with the scaffold question. Unlike phentermine, tesofensine produced few head-weaving stereotypies in that work [6].
What a PET paper is doing in this list
An indexed positron-emission paper measured striatal dopamine-transporter occupancy in people [10]. Human occupancy percentages and human dose ladders from that paper are outside the scope of this profile. The in-vitro IC50 values quoted above are the part that travels.
Keep [10] in the list so a reader can find it. Do not treat a human occupancy curve as a laboratory reconstitution guide.
Pharmacokinetics
The kinetic profile of this compound is its most distinctive feature and its most common omission.
Half-lives measured in weeks
Lehr and colleagues built a population pharmacokinetic model from 1,969 parent and 1,714 metabolite concentrations. The data came from 320 patients receiving multiple oral doses [8].
One-compartment models with first-order elimination described both species best. Low apparent clearance combined with large apparent volume of distribution produced half-lives of 234 hours for the parent compound and 374 hours for M1 [8].
The practical consequences are substantial. Accumulation continues for weeks before plasma concentrations plateau, so an early sample does not represent steady state. A washout period between crossover arms has to be measured in months rather than days.
Enterohepatic recycling
Plasma profiles for this compound show multiple peaks, which a simple absorption model cannot generate.
Lehr and colleagues developed a quantitative enterohepatic recycling model. It used intravenous tesofensine data from 21 healthy subjects given six-hour infusions (PMID 19705923) [9]. The profiles fitted best to a three-compartment model with a dedicated gallbladder compartment, released periodically under a sine-function control keyed to clock time [9].
Enterohepatic recycling explains both the multiple peaks and part of the prolonged apparent half-life. For laboratory work it means sampling schedules designed around a single absorption peak will misrepresent the exposure profile.
Covariates that shift exposure
The population model identified weight, sex, creatinine clearance, body mass index and age as influencing pharmacokinetics [8].
Simulation narrowed that list. Only creatinine clearance and sex produced significant effects on steady-state profiles. Females with a creatinine clearance of 35.6 mL/min showed 62 percent greater exposure than males without renal impairment [8].
Renal function driving exposure by that margin is worth noting in any study design that does not control for it.
The M1 metabolite
Lehr and colleagues characterised the metabolite’s contribution directly. They built a pharmacokinetic-pharmacodynamic model in 228 mice, dosing parent and metabolite separately by intravenous and oral routes. Dopamine transporter occupancy served as the readout [7].
The M1 metabolite showed half-maximal effective concentrations four to five times higher than parent, making it the weaker of the two in that mouse occupancy model. It also reached roughly eightfold higher steady-state concentrations. The authors concluded M1 contributes to overall activity in mice [7].
Those two sentences look like they disagree with the synaptosome table. They do not. Synaptosome IC50 values make M1 the tighter binder. The mouse occupancy model made M1 the weaker species on the in-vivo curve. Name the assay.
Pharmacokinetics were non-linear, with elimination and metabolism kinetics changing as dose rose [7]. Doubling the dose does not double exposure for this compound.
Preclinical obesity pharmacology
A substantial body of rodent work followed the clinical weight observation, and it is more mechanistically informative than the trials.
Comparison against established comparators
Hansen and colleagues treated diet-induced obese rats for 28 days, comparing tesofensine against sibutramine and rimonabant (PMID 20385125) [3].
Tesofensine produced dose-dependent sustained weight loss of 5.7 and 9.9 percent at two doses. Sibutramine produced 7.6 percent, and rimonabant produced only a transient reduction. The hypophagic effect of tesofensine lasted longer than either comparator [3].
One control deserves attention. Pair-fed animals received the same reduced food intake without the drug. They returned to baseline body weight by the end of the study, while treated animals did not [3]. That dissociation suggests the effect involves more than appetite suppression alone. The authors also reported suppressed insulin response on oral glucose tolerance testing below the level obtainable by paired feeding [3].
What the rodent file actually supports
Diet-induced obese rats, chow-fed controls and transgenic hypothalamic mice are different systems [2][3], [4][5] and [6]. Read-across between them is a claim that needs its own experiment.
A 28-day rat study that reports body weight has not reported D2/D3 availability. A microdialysis paper that reports accumbal dopamine has not reported lateral-hypothalamic ensembles. Name the model.
Bello and Zahner reviewed the triple reuptake inhibitor class around this analogue [1]. Use that review for chronology and synonyms. Do not use it as a use document.
Indexed papers outside this profile
The human history of this compound runs through two indications and a publishing controversy. This profile keeps the citations and leaves the endpoints out.
Parkinson, Alzheimer and obesity programmes
Rascol and colleagues ran the ADVANS study in advanced Parkinson disease [12]. Human rating-scale scores and human dose ladders from that paper are outside the scope of this profile.
Astrup and colleagues performed a meta-analysis of body weight across four randomised trials in Parkinson and Alzheimer disease [11]. Human weight-change percentages from that pool stay out.
Astrup and colleagues then ran a phase 2 obesity trial (PMID 18950853) [13]. Human obesity-trial outcomes from that paper stay out. The paper still belongs in the list because later correspondence and an editorial notice attach to it.
The Expression of Concern
Correspondence published in 2009 raised questions about cardiovascular and psychiatric reporting [14][15].
More consequentially, in 2013 the journal published an Expression of Concern regarding the trial [16]. An Expression of Concern is a formal editorial notice. It signals unresolved questions about a published paper. Such a notice is not a retraction, and it does not establish that the findings are wrong. The paper does, however, carry a standing editorial caveat from that point on.
Reviews of obesity pharmacotherapy from that period list tesofensine among first-in-class molecules whose clinical development had limited success [17]. Human authorisation language is outside this profile.
Abuse-liability paper
Because the scaffold resembles cocaine, a controlled paper in recreational stimulant users exists [18]. Human subjective scores from that paper are out of scope. A tropane scaffold does not by itself predict a stimulant profile. The rodent stereotypy observation in Perez and colleagues is the animal-facing half of the same question [6].
Physicochemical properties and handling
The molecule is a lipophilic tertiary amine carrying an ether linkage and no ester. It is chemically stable under ordinary storage, and the practical concerns are salt form and stereochemical integrity rather than degradation.
Confirm salt form before converting a weighed mass into moles. Free base and salt differ in molar content per gram. A citrate or hydrochloride salt changes the calculation substantially.
Store the solid sealed, dry, cold and dark.
Storage guidance is a house recommendation. Analytical documentation is per-lot release testing.
Dilute aqueous solutions need a pH note. The tertiary amine is protonated in acid and free in base. Solubility and surface adsorption both move with that equilibrium. Aliquot on dissolution rather than sampling one vial repeatedly.
Analytical characterisation
Four checks cover this compound, ranked by how much each changes the identity of the material.
What actually decides the lot
Stereochemical purity is first. Four defined centres mean several stereoisomers share the formula and accurate mass, and only a chiral method reports the difference.
The chlorine isotope envelope is the fastest confirmation. Two chlorines produce an M+2 peak near two thirds of the molecular ion intensity, with a clearly visible M+4. That pattern separates the compound at a glance from mono-chlorinated relatives.
Accurate mass confirms C17H23Cl2NO at 328.28.
Chromatographic purity is the figure most certificates lead with and the least informative of the four here.
What a rigorous certificate should contain
Chiral purity, by a stated method, with the value given.
Accurate mass with the isotope envelope shown, confirming exactly two chlorines.
Salt form, stated explicitly, with the counterion named.
Structural confirmation by NMR, establishing the tropane substitution pattern.
Kimera publishes third-party certificates of analysis for every lot in its COA database. Laboratories source Tesofensine as a reference triple reuptake inhibitor, sometimes alongside CE-123, a selective transporter inhibitor with a very different profile, or Adrafinil. Related chemistry appears in the metabolic category.
Common misclassifications
Four errors recur.
The compound is treated as a single chemical entity. M1 reaches roughly eightfold higher steady-state concentrations than parent and contributes to activity [7].
Its serotonergic component is assumed to drive the feeding effect. Antagonist work found the effect ran through alpha1 and D1 pathways, with a 5-HT2A/C antagonist producing no change [2].
Its tropane scaffold is read as implying stimulant liability. A controlled human paper exists [18]. Human scores stay out. The rodent stereotypy comparison is the part this profile keeps [6].
The obesity trial is cited without qualification. It carries a 2013 Expression of Concern from the publishing journal [16].
Experimental design considerations
Allow for the half-life. At 234 hours for parent and 374 hours for metabolite, steady state takes weeks and washout takes months [8].
Account for M1. A single-compound assumption misdescribes what is present after repeated dosing [7].
Expect non-linearity. Elimination and metabolism kinetics change with dose [7].
Sample for multiple peaks. Enterohepatic recycling produces profiles that a single-peak schedule will miss [9].
Record renal function and sex. Both shifted exposure materially in the population model [8].
Name the antagonist if a feeding study claims a pathway. Axel and colleagues already showed that a 5-HT2A/C block does not rescue the hypophagic effect in diet-induced obese rats [2].
Name the feeding control. Pair-fed animals in Hansen and colleagues returned to baseline while treated animals did not [3]. Intake-matching is not a formality on this analogue.
Frequently asked questions
What is Tesofensine? A tropane-derived triple monoamine reuptake inhibitor, CAS 195875-84-4, developed by NeuroSearch as NS 2330. Kimera supplies it as a laboratory research material.
Which transporters does it block? Dopamine, noradrenaline and serotonin [1].
How long is the half-life? About 234 hours for parent compound and 374 hours for the M1 metabolite [8].
What is M1? The major metabolite. Synaptosome IC50 values make it the tighter binder [7][10]. A mouse occupancy model made it four to five times less potent than parent at the dopamine transporter, while it still reached roughly eightfold higher steady-state concentrations [7].
Which receptors carry the rodent feeding effect? Alpha1 adrenoceptor and dopamine D1 pathways in diet-induced obese rats. A 5-HT2A/C antagonist did not block the effect [2].
Does this page report human occupancy or obesity-trial outcomes? No. Indexed papers exist [10][13]. Human endpoints are outside the scope of this profile.
Does the obesity trial stand unqualified? No. It carries a 2013 Expression of Concern [16] after published correspondence [14][15].
Summary of the evidence
Write the name, the formula and the three transporters on the first line of a notebook page. Everything else in this profile is a check on those three facts.
Identity: C17H23Cl2NO, 328.28 g/mol, tropane scaffold, four defined stereocentres, two chlorines. PubChem CID 11370864 and InChIKey VCVWXKKWDOJNIT-ZOMKSWQUSA-N close the record. A certificate that omits chiral purity is not finished.
Tesofensine is the long name for that lot. NS 2330 is the same molecule under a development code. Do not treat a code as a second compound.
If a methods section names Tesofensine and then skips the M1 metabolite, stop. After repeated exposure the vial is not a single-species experiment [7]. Keep the certificate next to the notebook. A later reader should be able to match the Tesofensine lot to the paper without asking you what was in the vial.
Mechanism: reuptake inhibition at all three monoamine transporters [1], with the feeding effect running through alpha1 adrenoceptor and D1 receptor pathways [2].
Kinetics: half-lives of 234 and 374 hours, non-linear with dose, with enterohepatic recycling producing multiple plasma peaks [7][8] and [9].
Preclinical obesity data: sustained weight loss exceeding rimonabant and comparable to or greater than sibutramine, with effects beyond matched food restriction [3]. Reversal of lowered forebrain dopamine [4]. Inhibition of GABAergic lateral hypothalamic neurons [6].
Limits: human doses, human pharmacodynamic endpoints and human obesity-trial outcomes are out of scope here. Those papers remain in the reference list.
Status: supplied for laboratory research use only.
References
- Bello NT, Zahner MR. Tesofensine, a monoamine reuptake inhibitor for the treatment of obesity. Curr Opin Investig Drugs. 2009;10(10):1105-1116. PMID 19777399
- Axel AM, Mikkelsen JD, Hansen HH. Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat. Neuropsychopharmacology. 2010;35(7):1464-1476. PMID 20200509. DOI
- Hansen HH, Hansen G, Tang-Christensen M, et al. The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant. Eur J Pharmacol. 2010;636(1-3):88-95. PMID 20385125. DOI
- Hansen HH, Jensen MM, Overgaard A, et al. Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat. Pharmacol Biochem Behav. 2013;110:265-271. PMID 23932919. DOI
- van de Giessen E, de Bruin K, la Fleur SE, et al. Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats. Eur Neuropsychopharmacol. 2012;22(4):290-299. PMID 21889317. DOI
- Perez CI, Luis-Islas J, Lopez A, et al. Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons. PLoS One. 2024;19(4):e0300544. PMID 38656972. DOI
- Lehr T, Staab A, Tillmann C, et al. Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach. Br J Pharmacol. 2008;153(1):164-174. PMID 17982477. DOI
- Lehr T, Staab A, Tillmann C, et al. Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer’s disease. Br J Clin Pharmacol. 2007;64(1):36-48. PMID 17324246. DOI
- Lehr T, Staab A, Tillmann C, et al. A quantitative enterohepatic circulation model: development and evaluation with tesofensine and meloxicam. Clin Pharmacokinet. 2009;48(8):529-542. PMID 19705923. DOI
- Appel L, Bergström M, Buus Lassen J, Långström B. Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET. Eur Neuropsychopharmacol. 2014;24(2):251-261. PMID 24239329. DOI
- Astrup A, Meier DH, Mikkelsen BO, Villumsen JS, Larsen TM. Weight loss produced by tesofensine in patients with Parkinson’s or Alzheimer’s disease. Obesity (Silver Spring). 2008;16(6):1363-1369. PMID 18356831. DOI
- Rascol O, Poewe W, Lees A, et al. Tesofensine (NS 2330), a monoamine reuptake inhibitor, in patients with advanced Parkinson disease and motor fluctuations: the ADVANS Study. Arch Neurol. 2008;65(5):577-583. PMID 18474731. DOI
- Astrup A, Madsbad S, Breum L, et al. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9653):1906-1913. PMID 18950853. DOI
- Tsai AG. Tesofensine and weight loss. Lancet. 2009;373(9665):719. PMID 19249625. DOI
- Sommet A, Pathak A, Montastruc JL. Tesofensine and weight loss. Lancet. 2009;373(9665):719. PMID 19249626. DOI
- Expression of concern: effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9873):1167. PMID 23561987. DOI
- George M, Rajaram M, Shanmugam E. New and emerging drug molecules against obesity. J Cardiovasc Pharmacol Ther. 2014;19(1):65-76. PMID 24064009. DOI
- Schoedel KA, Meier D, Chakraborty B, Manniche PM, Sellers EM. Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users. Clin Pharmacol Ther. 2010;88(1):69-78. PMID 20520602. DOI
Tesofensine is sold for laboratory research use only. Not for human consumption, nor medical, veterinary, or household uses.
Literature retrieved from PubMed.
