Complex interactions of sibutramine with α 1D ‐adrenoceptors

This study investigates the interactions of sibutramine, a hypophagic drug non‐selective inhibitor of norepinephrine (NE) and 5‐HT uptake, with the α 1 ‐ARs subtypes of the rat vas deferens (α 1A ), spleen (α 1B ) and aorta (α 1D ) and with human α 1 ‐ARs subtypes expressed in HEK 293 cells. Sibutramine potentiated the contractions induced by NE in the vas deferens, consistent with an indirect sympathomimetic action. In the rat spleen, sibutramine (up to 100 μM) was unable to affect the contractions induced by NE, suggesting it is inactive at α 1B ‐ARs. In rat aorta sibutramine 3 to 100 μM competitively antagonized the contractions induced by NE (Schild slope = 0.95 ± 0.05; pA 2 = 5.5 ± 0.1) indicating it interacts with α 1D ‐ARs. Sibutramine inhibited the specific binding of [ 3 H]‐prazosin to membranes from HEK cells expressing α 1A ‐ARs and α 1B ‐ARs with very low affinities (pK i ≈ 3.5). Low concentrations of sibutramine (30 nM to 1 μM) partially inhibited (≈50%) the specific binding of [ 3 H]‐prazosin to membranes from HEK cells expressing α 1D ‐ARs. In dissociation experiments, a low concentration of sibutramine (0.3 μM) increased by 5‐fold the dissociation of [ 3 H]‐prazosin from membranes of HEK cells expressing α 1D ‐ARs whereas sibutramine 10 μM delayed it by 3‐fold. Although presenting complex behavior in radioligand binding assays, sibutramine interacts selectively with native and recombinant α 1D ‐ARs.