Tesofensine

Tesofensine, development code NS2330, is a synthetic small molecule built on a tropane ring that blocks the reuptake of dopamine, norepinephrine and serotonin (Li et al., 2025). NeuroSearch and Boehringer Ingelheim first developed it for Parkinson's and Alzheimer's disease (Bello and Zahner, 2009), but phase II trials did not show a consistent effect (Hauser et al., 2007), and that development was discontinued (Perez et al., 2024).

Body weight fell in those trials, so it was then studied in obesity (Astrup et al., 2008).

PubChem CID 11370864 lists the same formula, weight and CAS number for the free base and supplies the synonyms and structure; the citrate salt is a separate record (CID 11421038, C₂₃H₃₁Cl₂NO₈, 520.4 g/mol).

Tesofensine research falls into six areas. Each summary names its model.

Monoamine transporter binding

Cryo-EM structures place tesofensine in the central binding pocket of the human dopamine (DAT), norepinephrine (NET) and serotonin (SERT) transporters, holding each in an outward-facing conformation. In DAT its tropane ring sits almost where cocaine's does, and the mutations F326A and S422A sharply cut its potency against [³H]dopamine uptake (Li et al., 2025).

In 228 mice given tesofensine, its main metabolite M1 or vehicle, intravenously or by mouth at 0.3 to 20 mg/kg, M1 was 4 to 5 times less potent at inhibiting DAT, yet the authors concluded it adds to tesofensine's overall activity (Lehr et al., 2008). Models: human transporters expressed in HEK-293F cells, and mice.

Food intake in diet-induced obese rats

In diet-induced obese (DIO) rats, 2.0 mg/kg subcutaneously for 16 days lowered food intake and body weight versus vehicle, and acute food intake fell as the amount rose from 0.5 to 3.0 mg/kg. The alpha1-adrenoceptor antagonist prazosin almost fully reversed this and the D1 antagonist SCH23390 partly did; alpha2, D2, D3 and 5-HT2A/2C antagonists did not (Axel et al., 2010).

Over 28 days at 1.0 or 2.5 mg/kg by mouth, body weight fell 5.7% and 9.9% from baseline. Pair-fed rats returned to baseline weight, which the authors read as a sign of higher energy expenditure (Hansen et al., 2010). Model: DIO rats.

Hypothalamic neurons and behavior

Tesofensine lowered body weight more in obese than in lean rats. In Vgat-ChR2 and Vgat-IRES-cre mice, it inhibited a subset of GABAergic neurons in the lateral hypothalamus and reduced their ability to promote feeding, and silencing those neurons chemogenetically strengthened its effect on food intake. Unlike phentermine, it produced little head-weaving stereotypy (Perez et al., 2024). Models: rats and transgenic mice.

Heart rate and blood pressure in rats

In conscious telemetered rats, tesofensine lowered food intake and raised heart rate and blood pressure. The beta-1 blocker metoprolol, at 10 to 20 mg/kg by mouth, fully prevented the cardiovascular changes without blunting the drop in food intake; telmisartan only partly reversed the rise in systolic pressure. The authors attribute the heart rate and blood pressure rises to increased sympathetic activity (Bentzen et al., 2013). Model: rats.

The Parkinson's and Alzheimer's disease program

In 261 people with early Parkinson's disease not yet on dopaminergic drugs, placebo or one of three daily amounts for 14 weeks gave no significant difference in total UPDRS change from baseline to week 14; a difference in the highest arm at week 6 was not sustained (Hauser et al., 2007).

In advanced disease, the 14-week ADVANS trial of placebo against four daily amounts found a significant difference on one of the two coprimary endpoints in each of two arms, no clear relationship between the amount given and efficacy, and more gastrointestinal and neuropsychiatric adverse events than placebo, especially in the higher arms (Rascol et al., 2008).

In Alzheimer's disease, a 14-week phase IIb trial in 430 participants was negative (Lehr et al., 2010). Development for both diseases was discontinued (Perez et al., 2024); a 2009 review calls tesofensine ineffective in these conditions (Bello and Zahner, 2009).

In a pooled analysis of four of the trials (968 participants), mean body weight rose 0.5% with placebo and fell 0.5% to 2.8% across the tesofensine arms, and heart rate rose by up to 6.8 beats per minute without a change in blood pressure (Astrup et al., 2008). Models: phase II clinical trials.

Obesity trials and reported adverse findings

The phase II obesity trial enrolled 203 adults with a body mass index of 30 to 40 on an energy-restricted diet, who received placebo or one of three daily amounts for 24 weeks. The primary outcome, percentage change in body weight, was a mean fall of 2.0% with placebo against 4.5%, 9.2% and 10.6% in the tesofensine arms. The 2008 report listed the most common adverse events as dry mouth, nausea, constipation, hard stools, diarrhea and insomnia.

Heart rate rose 7.4 beats per minute in the middle arm; the two lower arms showed no significant rise in blood pressure (Astrup et al., 2008), and a review reported significant increases in the highest arm (Bello and Zahner, 2009). In 2013 The Lancet attached an expression of concern to the report (Lancet, 2013), and the authors followed with a letter titled "Under-reporting of adverse effects of tesofensine" (Astrup et al., 2013).

A later 24-week trial tested tesofensine with metoprolol (Tesomet) in 21 adults with hypothalamic obesity. Sleep disturbances, dry mouth and headache were more common than with placebo, and one participant stopped the study drug after a serious worsening of pre-existing anxiety. Heart rate and blood pressure did not differ significantly between groups; body weight fell a mean 6.3% more than with placebo (Huynh et al., 2022). Models: randomized, placebo-controlled trials in adults.