Sibutramine Anorectics

A link between 5-HT transmission and hypophagia is further reinforced by the pharmacology of drugs that reduce food intake ( anorectic agents), such as (7-fenfluramine or sibutramine. Both these compounds have actions that should lead to increased synaptic concentrations of 5-HT in the brain, albeit through different mechanisms (see below), but whether or not this actually explains the anorectic actions of (7-fenfluramine is controversial. 

The adverse effects of amphetamine and related sympathomimetic appetite suppressants are well documented. All of these agents are classified by the U.S. Drug Enforcement Administration (DEA) as controlled substances (classes II-IV) according to their potential for causing addiction (see Table 15.4). Class II agents such as amphetamine are highly abused, with prescription restricted to speeial circumstances class TV anorectic drugs such as sibutramine, phentermine, di-ethylpropion, and mazindol have minimal abuse potential. 

The pharmacological activities of sibutramine metabolites have been evaluated. The R-enantiomers of BTS 54 354 and BTS 54 505 (44 and 46) show potent NE, 5-HT, and DA reuptake inhibitory activities, with IC50 values less than 13 and 140 nAf for NE reuptake inhibition and 5-HT reuptake inhibition, respectively (see Table 15.10) (71). The S-enantiomer of BTS 54 354 (45) exhibits weak inhibitory activity for inhibition of uptake of NE, 5-HT, and DA, whereas the S-isomer of BTS 54 505 (47) displays good activity for inhibition of NE and DA reuptake. Sibutramine metabolites may be primarily responsible for the potent anorectic activity of the parent drug. 

Sibutramine failed to show antidepressant activity in humans, but was found to be a potent anorectic agent. A structurally distinct compound, venlafaxine (81), with similar in vitro... 

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