Safety pharmacology of sibutramine analogues evaluated by in silico and in vitro biological target screening

Many weight loss products marketed as foods and dietary supplements are adulterated with structurally modified versions (analogues) of sibutramine, a weight loss drug withdrawn from the market due to adverse effects in the heart and nervous system. Unlike sibutramine, its analogues lack in vitro and in vivo safety data. Therefore, to identify potential health effects of sibutramine analogues, binding was predicted and measured between sibutramine analogues and a panel of 45 safety-related biological targets (e.g., receptors, ion channels, transporters, and enzymes) related to the heart, nervous system, and other organs. Target binding concentrations (K_i) were predicted in silico based upon quantitative structure-activity relationship (QSAR) models and measured in vitro by competitive ligand binding assays. The in vitro and in silico K_i values closely agreed for transporters of serotonin (SERT), norepinephrine (NET), and dopamine (DAT), which are linked to adverse health effects in the heart and nervous system. The chloro, homo, and desmethylsibutramine analogues exhibited similar binding profiles and particularly potent binding to SERT, NET and DAT (K_i, 9–403 nM). However, despite structural similarity among the compounds, benzyl and formyl analogues exhibited weaker binding to nearly all targets evaluated (K_i, 0.447 to >10 μM). Additionally, for selected analogues, target binding was predicted for metabolites; a majority of metabolites (70 %) exhibited similar binding potency (K_i within 10-fold) to their respective parent chemicals, suggesting they may also contribute to potential health effects. Overall, biological target binding profiles illustrate important structure-activity relationships among sibutramine analogues that can help identify potential adverse health effects.