Tesofensine is a novel monoamine reuptake inhibitor that inhibits both
norepinephrine,
5-HT, and
dopamine (DA) reuptake function.
Tesofensine is currently in clinical development for the treatment of
obesity, however, the pharmacological basis for its strong effect in
obesity management is not clarified. Using a rat model of diet-induced
obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect of
tesofensine. DIO rats treated with
tesofensine (2.0 mg/kg, s.c.) for 16 days showed significantly lower
body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized food intake monitoring system during a 12 h nocturnal test period,
tesofensine-induced hypophagia was investigated further by studying the acute interaction of a variety of monoamine receptor antagonists with
tesofensine-induced hypophagia in the DIO rat.
Tesofensine (0.5-3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED(50) of 1.3 mg/kg. The hypophagic response of
tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of
prazosin (1.0 mg/kg, alpha(1)
adrenoceptor antagonist) and partially antagonized by co-administration of
SCH23390 (0.03 mg/kg, DA D(1) receptor antagonist). In contrast,
tesofensine-induced hypophagia was not affected by
RX821002 (0.3 mg/kg, alpha(2)
adrenoceptor antagonist),
haloperidol (0.03 mg/kg, D(2) receptor antagonist), NGB2904 (0.1 mg/kg, D(3) receptor antagonist), or
ritanserin (0.03 mg/kg, 5-HT(2A/C) receptor antagonist). Hence, the mechanism underlying the suppression of feeding by
tesofensine in the obese rat is dependent on the
drug's ability to indirectly stimulate alpha(1)
adrenoceptor and DA D(1) receptor function.