Enantioselective behavioral effects of sibutramine metabolites

The anti-obesity agent, racemic (RS)-sibutramine, has two active metabolites, desmethylsibutramine and didesmethylsibutramine. To the extent that sibutramine itself mediates some of its side effects, desmethylsibutramine and/or didesmethylsibutramine might be safer and just as therapeutically effective. Because both desmethylsibutramine and didesmethylsibutramine are also optically active, the present study assessed the anorexic effects (2.5-10 mg/kg, i.p., for all drugs), in rats, of the R(+)-and S(-)-enantiomers of both metabolites and compared them to the effects of racemic sibutramine. Locomotor activity (2.5-10 mg/kg, i.p., for all drugs), a dopamine dependent behavior, was also measured in view of some uncertainty regarding dopaminergic effects of sibutramine. In view of sibutramine's antidepressant profile in animal models, the same drugs were also tested in the Porsolt swim test (0.1-2.5 mg/kg, i.p., for all drugs). Lastly, the IC(50)s of all drugs to inhibit uptake in vitro of norepinephrine, serotonin and dopamine were determined. Both (R)-enantiomers had significantly greater anorexic effects than those of their respective (S)-enantiomers as well as of sibutramine. All of the agents increased locomotor activity and reduced immobilized time ("behavioral despair") in the swim test; again, the (R)-enantiomers were more potent than the (S)-enantiomers and sibutramine. However, the anorexic and locomotor effects could be dissociated from each other as well as from effects in the swim test. Both (R)-desmethylsibutramine and (R)-didesmethybibutramine as well as sibutramine decreased food intake at a time (24-42 h post-treatment) when locomotor activity was unaffected. All of the drugs appeared to be more potent in the swim test than in the other tests and all of the drugs were more potent at inhibiting uptake of norepinephrine and dopamine than of serotonin. The results suggest that these enantioselective metabolites of sibutramine could be safe and effective treatments for obesity as well as possibly for depression. (C) 2000 Elsevier Science B.V. All rights reserved.