title: Search for novel leads for histamine H3-receptor antagonists: oxygen-containing derivatives.
abstract: This study was performed in order to develop new leads for antagonists of the histamine H3-receptor subtype. omega-(1 H-Imidazol-4-yl)alkyl derivatives with ester, ketone or alcohol functionality in the side chain were synthesized and tested concerning their H3-receptor antagonist activity on synaptosomes of rat cerebral cortex. The novel compounds, which possess no nitrogen-containing polar group in the side chain of the imidazole moiety, presented moderate to high antagonist potency in vitro. In this series 3-(1 H-imidazol-4-yl)propyl-3-cyclopentylpropanoate (4) was the most potent compound in vitro with -log Ki = 8.5. Unfortunately, no central antagonist H3-receptor activity was detectable for ester derivatives in the in vitro H3-receptor assay based upon measurement of brain N tau-methylhistamine levels after p.o. administration to mice. Some of these novel antagonists are useful tools for investigations on ligand-receptor interaction because of their distinct receptor activities. On the other hand, the ketone derivative 1-(1 H-imidazol-4-yl)-7-phenyl-4-heptanone (9) in vitro presented an ED50-value of 3.5 +/- 1.5 mg/kg p.o. thus proving to be a new lead for further drug investigations. The most potent compounds in vitro and in vivo also showed high H3-receptor selectivity when tested at other histamine receptor subtypes.
authors.affiliation: Institut für Pharmazie I Freie Universität Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.forename: A
authors.initials: A
authors.lastname: Hüls
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: J M
authors.initials: JM
authors.lastname: Arrang
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: W
authors.initials: W
authors.lastname: Schunack
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000737:chemistry; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*
chemical_list: D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D008761:Methylhistamines; D018100:Receptors, Histamine H3; D010100:Oxygen; C048140:N-methylhistamine