In vitro and in vivo pharmacological analysis of imidazole-free histamine H3 receptor antagonists: promising results for a brain-penetrating H3 blocker with weak anticholinesterase activity.

The pharmacological profiling of potent histamine H(3)-ligands initiated in a previous study is completed here. In vitro functional and binding studies revealed that several derivatives were selective H(3)-antagonists with nanomolar potency at human and guinea-pig histamine receptors, able to inhibit rat brain cholinesterase at micromolar concentrations and devoid of any cytotoxicity on cultured cells. Ex vivo binding experiments in rats showed that the most potent H(3)-antagonist, compound 5, had a prompt and long-lasting presence in the central nervous system (CNS), inhibiting [(3)H](R)-alpha-methylhistamine cortical binding [ED(50) (dose that elicits a 50% response) = 0.63 mg/kg intraperitoneally (i.p.)]. In the passive-avoidance test, compound 5, at 1.25 mg/kg i.p., was as effective as the anti-Alzheimer drug donepezil in attenuating scopolamine-induced amnesia in rats. These results suggest that a good CNS penetration and multitarget activity could account for the antiamnesic effect of this weak cholinesterase inhibitor and potent H(3)-antagonist (compound 5). This result represents a potential benchmark for the development of non-imidazole H(3)-antagonists/cholinesterase inhibitors with therapeutic potential in cognitive disorders.