title: Novel nonimidazole histamine H3 receptor antagonists: 1-(4-(phenoxymethyl)benzyl)piperidines and related compounds.
abstract: In an extension of very recently published studies on successful imidazole replacements in some series of histamine H(3) receptor antagonists, we report on a new class of lipophilic nonimidazole antagonist having an aliphatic tertiary amino moiety connected to a benzyl template substituted in the 4-position by a phenoxymethyl group. The structural modifications were performed with the intention to avoid possible negative side effects reported for other series of antagonists. The novel compounds combine different characteristics of recently developed histamine H(3) receptor antagonists. The compounds were screened for their affinity in a binding assay for the human histamine H(3) receptor stably expressed in CHO-K1 cells and tested for their in vivo potency in the central nervous system of mice after oral administration. Different substitution patterns on the phenoxy group were used to optimize in vitro and/or in vivo potency leading to some compounds with low nanomolar affinity and high oral in vivo potency. Modifications of the basic piperidino moiety were performed by ring expansion, contraction, and opening. Selected compounds exhibited selectivity in functional assays on isolated organs of guinea-pig for H(3) vs H(1) and H(2) receptors. Unexpectedly, some of the novel antagonists also showed a slight preference for the human histamine H(3) receptor compared to their affinities for the guinea-pig H(3) receptor.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Mikó
authors.forename: Xavier
authors.initials: X
authors.lastname: Ligneau
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Pertz
authors.forename: C Robin
authors.initials: CR
authors.lastname: Ganellin
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Arrang
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: D000818:Animals; D016275:Atrial Function / Q000187:drug effects; D001667:Binding, Competitive; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006633:Histamine Antagonists; D008761:Methylhistamines; D010880:Piperidines; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; C031205:3-methylhistamine