title: Imidazole derivatives as a novel class of hybrid compounds with inhibitory histamine N-methyltransferase potencies and histamine hH3 receptor affinities.
abstract: In this study, a novel series of imidazole-containing compounds with dual properties, that is, inhibitory potency at the enzyme histamine N(tau)-methyltransferase (HMT) and antagonist potency at histamine H(3) receptors was designed and synthesized. Pharmacologically, these new hybrid drugs were evaluated in functional assays for their inhibitory potencies at rat kidney HMT and for their antagonist activities on synaptosomes of rat cerebral cortex. For selected compounds, binding affinities at recombinant human histamine H(3) receptors were determined. The first compounds (1-10) of the series proved to be H(3) receptor ligands of high potency at rat synaptosomes or of high binding affinity at human H(3) receptors, respectively, but of only moderate activity as inhibitors of rat kidney HMT. In contrast, aminoquinoline- or tetrahydroacridine-containing derivatives 11-17 also displayed HMT inhibitory potency in the nanomolar concentration range. Preliminary data from molecular modeling investigations showed that the imidazole derivative 15 and the HMT inhibitor quinacrine possess identical binding areas. The most interesting compound (14) is simultaneously a highly potent H(3) receptor ligand (K(i)=4.1nM) and a highly potent HMT inhibitor (IC(50)=24nM), which makes this derivative a valuable pharmacological tool for further development.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Grassmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Apelt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Xavier
authors.initials: X
authors.lastname: Ligneau
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Pertz
authors.forename: Yuan Hui
authors.initials: YH
authors.lastname: Zhao
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Arrang
authors.forename: C Robin
authors.initials: CR
authors.lastname: Ganellin
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Schwartz
authors.forename: Walter
authors.initials: W
authors.lastname: Schunack
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D006633:Histamine Antagonists; D007093:Imidazoles; D018100:Receptors, Histamine H3; D006637:Histamine N-Methyltransferase; D011796:Quinacrine