N-Alkenyl and cycloalkyl carbamates as dual acting histamine H3 and H4 receptor ligands

Article abstract of DOI:10.1016/j.bmc.2011.03.046

Previous studies have shown that several imidazole derivatives posses affinity to histamine H₃ and H₄ receptors. Continuing our study on structural requirements responsible for affinity and selectivity for H₃/H₄ receptor subtypes, two series of 3-(1H-imidazol-4-yl)propyl carbamates were prepared: a series of unsaturated alkyl derivatives (1-9) and a series possessing a cycloalkyl group different distances to the carbamate moiety (10-13). The compounds were tested for their affinities at the human histamine H₃ receptor, stably expressed in CHO-K1 cells. Compounds 1, 2, 5-7, 10-13 were investigated for their affinities at the human histamine H₄ receptor co-expressed with Gα_i2 and Gβ₁γ₂ subunits in Sf9 cells. To expand the pharmacological profile, compounds were further tested for their H₃ receptor antagonist activity on guinea pig ileum and in vivo after oral administration to mice. All tested compounds exhibited good affinity for the human histamine H₃ receptor with K_i values in the range from 14 to 194 nM. All compounds were active in vivo after peroral administration (p.o.) to Swiss mice, thus demonstrating their ability to cross the blood-brain barrier. The most potent H₃ receptor ligand of these series was compound 5, 3-(1H-imidazol-4-yl)propyl pent-4-enylcarbamate with the highest affinity (K_i = 14 nM). Additionally, compound 3 showed remarkable central nervous system (CNS) H₃R activity, increasing the N^τ-methylhistamine levels in mice with an ED ₅₀ value of 0.55 mg/kg, p.o. evidencing therefore, a twofold increase of inverse agonist/antagonist potency compared to the reference inverse agonist/antagonist thioperamide. In this study, the imidazole propyloxy carbamate moiety was kept constant. The different lipophilic moieties connected to the carbamate functionality in the eastern part of the molecule had a range of influences on the human H₄ receptor affinity (154-1326 nM).