Tesofensine

Tesofensine is a novel serotonin-noradrenaline-dopamine reuptake inhibitor (SNDRI) originally developed by NeuroSearch for neurological conditions (Alzheimer's and Parkinson's disease) before its potent weight-reducing effects were identified during clinical trials. It inhibits the presynaptic reuptake of all three monoamine neurotransmitters — serotonin (5-HT), norepinephrine (NE), and dopamine (DA) — with relative potencies of approximately 1:2:3 (DA>NE>5-HT). This triple reuptake inhibition produces synergistic effects on appetite suppression through hypothalamic satiety center activation, thermogenesis enhancement through sympathetic nervous system stimulation, reward circuit modulation that reduces food-seeking behavior, and potential improvement in mood and motivation. Phase II clinical trials demonstrated average weight reductions of 10-13% over 24 weeks — among the largest reductions observed for any pharmacological intervention at the time. Research applications include studies on monoamine signaling in appetite regulation, comparative pharmacology of selective versus non-selective reuptake inhibitors, CNS mechanisms of food intake control, and the relationship between dopaminergic reward signaling and eating behavior.