Brain penetration of the histamine H3 receptor antagonists thioperamide and clobenpropit in rat and mouse, determined with ex vivo [125I]iodophenpropit binding.

We investigated the brain penetration of the histamine H3 receptor antagonists thioperamide and clobenpropit using ex vivo [125I]iodophenpropit binding. Homogenates of the rat cortex, striatum and mouse whole brain were prepared 1 h after subcutaneous injection of the H3 antagonists and incubated with [125I]iodophenpropit, a radiolabeled H3 receptor antagonist, to determine the H3 receptor occupancy. Specific [125I]iodophenpropit binding to the rat cortex and striatum was inhibited by thioperamide with IC30 values of 1.0 and 1.5 mg/kg, respectively. Clobenpropit also inhibited [125I]iodophenpropit binding, but was less potent (IC30: 18 and 19 mg/kg in the rat cortex and striatum, respectively) than thioperamide. Similar results were obtained in experiments with mouse whole brain (3.5 and 13 mg/kg for thioperamide and clobenpropit), indicating that there is no important species differences in the brain penetration of these drugs between rats and mice. These findings suggest that after peripheral injection both in rat and mouse thioperamide penetrates the blood-brain barrier more efficiently compared to clobenpropit.