title: Piperidino-hydrocarbon compounds as novel non-imidazole histamine H(3)-receptor antagonists.
abstract: In search for novel non-imidazole histamine H(3)-receptor antagonists, piperidino-hydrocarbon compounds were synthesized using the known non-imidazole histamine H(3)-receptor antagonist FUB 637 (3-phenylpropyl 3-piperidinopropyl ether) as lead structure. Piperidino-alkyl derivatives containing highly flexible side chains (2, 4-7) were prepared via N-alkylation. Compounds containing unsaturated alkyl groups were synthesized in order to investigate the impact of rigidifying the side chain (8-16). Terminal alkynes were prepared by alkylation of lithium acetylide-ethylenediamine complex, disubstituted alkynes were synthesized by alkylation of the appropriate acetylene in the presence of n-butyllithium-N,N,N',N'-tetramethylene-ethylene-diamine complex. The novel compounds were investigated in an in vitro functional assay on the guinea-pig ileum, in which N-(7-phenylhept-3-ynyl)piperidine (14) proved to be of good potency in this class (pA(2)=7.21). In an in vivo assay the compounds were additionally screened for their abilities to influence central H(3)-histaminergic neuron activity in mice with regard to their oral availabilities and distribution properties. In this screening, N-pent-4-ynylpiperidine (9) and N-hex-5-ynylpiperidine (10) proved to be highly potent and orally available histamine H(3)-receptor antagonists. The ED(50) values for 9 and 10 were 1.3 and 1.4mg/kg po, respectively, which is in the potency range of the reference antagonist thioperamide.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany.
authors.forename: Galina
authors.initials: G
authors.lastname: Meier
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-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: D000284:Administration, Oral; D000478:Alkylation; D000818:Animals; D001682:Biological Availability; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007082:Ileum / Q000378:metabolism; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3