title: New high affinity H3 receptor agonists without a basic side chain.
abstract: In this study, we replaced the basic amine function of the known histamine H(3) receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H(3) receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H(3) receptor over the human H(4) receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H(3) receptor agonist (pK(i) = 8.0 and pEC(50) = 8.1) with a 320-fold selectivity at the human H(3) receptor over the human H(4) receptor.
authors.affiliation: Leiden/Amsterdam Center of Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit Amsterdam, The Netherlands.
authors.forename: Ruengwit
authors.initials: R
authors.lastname: Kitbunnadaj
authors.forename: Marcel
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Silvina A
authors.initials: SA
authors.lastname: Fratantoni
authors.forename: Gerold
authors.initials: G
authors.lastname: Bongers
authors.forename: Remko A
authors.initials: RA
authors.lastname: Bakker
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wieland
authors.forename: Ahmed
authors.initials: A
authors.lastname: el Jilali
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: De Esch
authors.forename: Wiro M P B
authors.initials: WM
authors.lastname: Menge
authors.forename: Henk
authors.initials: H
authors.lastname: Timmerman
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D045744:Cell Line, Tumor; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D017442:Histamine Agonists; D011968:Receptors, Histamine