title: N-Alkenyl and cycloalkyl carbamates as dual acting histamine H3 and H4 receptor ligands.
abstract: Previous studies have shown that several imidazole derivatives possess 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 H(3) 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 Gα(i2) and Gβ(1)γ(2) subunits in Sf9 cells. To expand the pharmacological profile, compounds were further tested for their H(3) 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 194nM. 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)=14nM). Additionally, compound 3 showed remarkable central nervous system (CNS) H(3)R activity, increasing the N(τ)-methylhistamine levels in mice with an ED(50) value of 0.55mg/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 (154-1326nM).
authors.affiliation: Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Więcek
authors.forename: Tim
authors.initials: T
authors.lastname: Kottke
authors.forename: Xavier
authors.initials: X
authors.lastname: Ligneau
authors.forename: Walter
authors.initials: W
authors.lastname: Schunack
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Handzlik
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002219:Carbamates; D006633:Histamine Antagonists; D008024:Ligands; C560331:N-((E)-hex-2-enyl)phthalimide; D010797:Phthalimides; D020033:Protein Isoforms; D018100:Receptors, Histamine H3