title: Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity.
abstract: The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4-yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log Ki values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED(50) values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.forename: K
authors.initials: K
authors.lastname: Purand
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: A
authors.initials: A
authors.lastname: Rouleau
authors.forename: J M
authors.initials: JM
authors.lastname: Arrang
authors.forename: M
authors.initials: M
authors.lastname: Garbarg
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: W
authors.initials: W
authors.lastname: Schunack
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D048448:Phenylcarbamates; D051381:Rats; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: C098655:3-(1H-imidazol-4-yl)propyl N-(4-fluorophenyl)carbamate; C098656:3-(1H-imidazol-4-yl)propyl N-benzylcarbamate; C098654:3-(1H-imidazol-4-yl)propyl N-phenylcarbamate; D002219:Carbamates; D006633:Histamine Antagonists; D007093:Imidazoles; D048448:Phenylcarbamates; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D006632:Histamine