title: Search for novel leads for histamine H3-receptor antagonists: amine derivatives.
abstract: In search for novel leads for histamine H3-receptor antagonists a number of amine derivatives of different (1 H-imidazol-4-yl)anilines and omega-(1 H-imidazol-4-yl)alkanamines were prepared. Pharmacological in vitro H3-receptor investigations of the prepared urea, amide, inverse amide, thioamide, and thiourea derivatives on synaptosomes of rat cerebral cortex proved that the aniline derivatives are inactive at H3-receptors, whereas derivatives of the omega-(1 H-imidazol-4-yl)-alkanamines showed moderate to good activity. Some compounds are active in the nanomolar concentration range. The most potent compounds in this series are the thioamide derivative 7 and the urea derivatives 11, 12 of 3-(1 H-imidazol-4-yl) propanamine. Therefore, the urea derivatives were tested in vitro on isolated organs of the guinea pig for their activity on the other two histamine receptor subtypes proving their high selectivity. In vivo studies of the effects of the urea derivatives 11 and 12 on brain Nt-methylhistamine levels, a test of central H3-receptor activity after peroral application to mice, showed no detectable activity. Thus, the urea type antagonists are useful potent and selective H3-receptor tools for in vitro studies and for investigations of ligand-receptor interactions.
authors.affiliation: Institut für Pharmazie I, Freie Universität Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: R
authors.initials: R
authors.lastname: Lipp
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; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006633:Histamine Antagonists / Q000138:chemical synthesis*; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008024:Ligands; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D011863:Radioimmunoassay; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*
chemical_list: D006633:Histamine Antagonists; D006635:Histamine H2 Antagonists; D008024:Ligands; D008761:Methylhistamines; D018100:Receptors, Histamine H3; C048140:N-methylhistamine