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BACKGROUND: Clobenpropit, a potent antagonist/inverse agonist at the histamine H3 receptor (H3R), reduced the cytotoxic action of 6-hydroxydopamine (6-OHDA) in neuroblastoma SH-SY5Y cells transfected with the human H3R. We therefore set out to study whether this effect involved a receptor-independent action on dopamine transport. METHODS: The uptake of [3H]-dopamine was assayed in SH-SY5Y cells and rat striatal or cerebro-cortical isolated nerve terminals (synaptosomes). Clobenpropit binding to the human norepinephrine (NET) and dopamine (DAT) transporters was analyzed by molecular modeling. RESULTS: In SH-SY5Y cells, [3H]-dopamine uptake was inhibited by desipramine (selective NET inhibitor), GBR-12909 (selective DAT inhibitor), and fluoxetine (selective inhibitor of the serotonin transporter, SERT) with IC50 values 37, 537, and 2800nM, respectively. The potency rank order indicates that [3H]-dopamine uptake is primarily performed by NET. Clobenpropit inhibited [3H]-dopamine uptake (maximum inhibition 82.7±2.8%, IC50 490nM), and the effect was reproduced by the H3R antagonist/inverse agonist iodophenpropit, but not by the agonists R-α-methylhistamine and immepip or the antagonists/inverse agonists ciproxifan and A-331440. Clobenpropit also inhibited [3H]-dopamine uptake by rat striatal and cerebro-cortical synaptosomes (-54.6±11.3% and -46.3±9.6%, respectively, at 10μM). Modeling of the human NET and DAT obtained by homology from the crystal of Drosophila melanogaster DAT showed that clobenpropit can bind to a site also recognized in both transporters by nisoxetine, a potent NET inhibitor. CONCLUSION: These data indicate a direct inhibitory effect of clobenpropit on catecholamine transport.

Original publication




Journal article


Pharmacol Rep

Publication Date





146 - 155


Clobenpropit, Dopamine transporter, Histamine H(3) receptor, Norepinephrine transporter, SH-SY5Y cells, Animals, Binding Sites, Brain, Cell Line, Tumor, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Dose-Response Relationship, Drug, Drosophila Proteins, Drug Inverse Agonism, Histamine H3 Antagonists, Humans, Imidazoles, Molecular Docking Simulation, Norepinephrine Plasma Membrane Transport Proteins, Protein Binding, Protein Conformation, Rats, Receptors, Histamine H3, Synaptosomes, Thiourea