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

Previous studies have shown that several imidazole derivatives posses affinity to histamine H-3 and H-4 receptors. Continuing our study on structural requirements responsible for affinity and selectivity for H-3/H-4 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 H-4 receptor co-expressed with G alpha(i2) and G beta(1)gamma(2) 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 H-3 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 H-3 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-tau-methylhistamine levels in mice with an ED50 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 H-4 receptor affinity (154-1326 nM). (C) 2011 Elsevier Ltd. All rights reserved.