title: Novel partial agonists for the histamine H(3) receptor with high in vitro and in vivo activity.
abstract: Novel branched N-alkylcarbamates and aliphatic ethers derived from 3-(1H-imidazol-4-yl)propanol were prepared. The compounds were investigated on two functional histamine H(3)-receptor assays. Some compounds displayed partial agonist activity on synaptosomes of rat brain cortex but behaved as pure competitive antagonists on the guinea pig ileum. Under in vivo conditions after po application to mice, some of the compounds showed partial or full agonist activity. Highest in vivo potency was found for the 3,3-dimethylbutyl ether 10 (ED(50) = 0.29 mg/kg, full intrinsic activity). These novel agonists are structurally diverse from classical aminergic histamine H(3)-receptor agonists (e.g., (R)-alpha-methylhistamine, imetit) as they lack a basic moiety in the side chain, which is supposed to be important for the activation of the receptor protein. The selectivity for the histamine H(3) receptor was proven by determination of H(1)- and H(2)-receptor activity on functional assays of the guinea pig.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sasse
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.forename: S
authors.initials: S
authors.lastname: Reidemeister
authors.forename: A
authors.initials: A
authors.lastname: Hüls
authors.forename: S
authors.initials: S
authors.lastname: Elz
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: C R
authors.initials: CR
authors.lastname: Ganellin
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: W
authors.initials: W
authors.lastname: Schunack
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure; D004558:Electric Stimulation; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
chemical_list: C122086:3-(1H-imidazol-4-yl)propyl 3,3-dimethylbutyl ether; D004987:Ethers; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D006632:Histamine; C020404:tele-methylhistamine