A promising imidazole-free histamine H3 receptor antagonist with good brain penetration and anticholinesterase activity.

Histamine H3 antagonists, lacking the imidazole ring that is associated with the drawbacks of CYP450 inhibition and low CNS access, have been recently proposed as a new therapeutic approach to several cognitive disorders characterized by deficit of neurotransmitter release such as Alzheimer disease, a pathology currently treated with cholinesterase (ChE) inhibitors. In the search for an improved treatment, a new biphenylic derivative five has been developed (Morini et al., 2006) as agent combining anticholinesterase activity with H3 histamine receptor inhibition. The selectivity, affinity and potency at H3 receptors and the inhibition of ChE were studied in vitro. The ability to enter the CNS (ex vivo binding) and to exert anti-amnesic activity (passive avoidance test) were investigated in 200–250 g female Wistar rats, applying experimental procedures supervised and approved by the Ministero della Salute (DL116/92). The in vitro results are summarized in Table 1. In ex vivo study compound 5 was 3 fold more potent than the conventional H3-blocker thioperamide in inhibiting [3H](R)-a-methylhistamine cortical binding (ED50 = 0.63 vs. 2.04 mg/kg i.p.). At 1.25 mg/kg i.p. it was as effective as the anti- Alzheimer drug donepezil and 7 fold more potent than thioperamide in reverting scopolamine-induced amnesia. These results suggest that the good CNS penetration and the dual inhibition of cholinesterase and histamine H3-receptors could account for the antiamnesic effect of compound 5, a potential benchmark for the development of non-imidazole H3-antagonists with therapeutic potential in cognitive disorders. Reference: Morini et al. Bioorg Med Chem Lett. 2006; 16: 4063