title: Influence of imidazole replacement in different structural classes of histamine H(3)-receptor antagonists.
abstract: The reference compounds for histamine H(3)-receptor antagonists carry as a common feature an imidazole moiety substituted in the 4-position. Very recently novel ligands lacking an imidazole ring have been described possessing a N-containing non-aromatic heterocycle instead. In this study we investigated whether imidazole replacement, favourably by a piperidine moiety, is generally applicable to different structural classes of reference compounds, e.g., thioperamide, carboperamide, clobenpropit, FUB 181, ciproxifan, etc. While replacement led to a loss of affinity for many of the compounds, it was successfully applied to some ether derivatives. The piperidine analogues of FUB 181 and ciproxifan, 3-(4-chlorophenyl)propyl 3-piperidinopropyl ether hydrogen oxalate (6) and cyclopropyl 4-(3-piperidinopropyloxy)phenyl methanone hydrogen maleate (7), almost maintained in vitro affinities, pK(i) values of 7.8 and 8.4, respectively, and showed high potency in vivo after p.o. administration (ED(50) values of 1.6 and 0.18 mg/kg, respectively).
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195, Berlin, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Meier
authors.forename: J
authors.initials: J
authors.lastname: Apelt
authors.forename: U
authors.initials: U
authors.lastname: Reichert
authors.forename: S
authors.initials: S
authors.lastname: Grassmann
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: S
authors.initials: S
authors.lastname: Elz
authors.forename: F
authors.initials: F
authors.lastname: Leurquin
authors.forename: C R
authors.initials: CR
authors.lastname: Ganellin
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: W
authors.initials: W
authors.lastname: Schunack
authors.forename: H
authors.initials: H
authors.lastname: Stark
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D006633:Histamine Antagonists; D007093:Imidazoles; D007202:Indicators and Reagents; D018100:Receptors, Histamine H3; D003577:Cytochrome P-450 Enzyme System