title: Mutational analysis of the histamine H1-receptor binding pocket of histaprodifens.
abstract: Histaprodifens constitute a new class of histamine H(1)-receptor agonists. These ligands can be regarded as hybrid molecules, consisting of a histamine moiety linked at the two-position of the imidazole ring by a propyl chain to two phenyl rings, one of the characteristic features of several H(1)-receptor antagonists. To delineate the binding site of various histaprodifen-like ligands, we generated mutant histamine H(1) receptors, in which various amino acids, involved in the binding of either histamine or H(1)-receptor antagonists, were replaced by alanine. Wild-type and mutant H(1) receptors were transiently expressed in African green monkey kidney cells (COS-7) and evaluated for their interaction with histamine and various histaprodifens by [(3)H]mepyramine radioligand-binding studies and by nuclear factor kappaB (NF-kappaB) reporter-gene assays. Our data show that, within the histamine H(1)-receptor binding pocket, histaprodifens interact with both agonist and antagonist binding sites, resulting in high affinity histamine H(1)-receptor agonists.
authors.affiliation: Leiden Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Bruysters
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Pertz
authors.forename: Aloys
authors.initials: A
authors.lastname: Teunissen
authors.forename: Remko A
authors.initials: RA
authors.lastname: Bakker
authors.forename: Michel
authors.initials: M
authors.lastname: Gillard
authors.forename: Pierre
authors.initials: P
authors.lastname: Chatelain
authors.forename: Walter
authors.initials: W
authors.lastname: Schunack
authors.forename: Henk
authors.initials: H
authors.lastname: Timmerman
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter / Q000235:genetics; D006632:Histamine / Q000031:analogs & derivatives* / Q000378:metabolism*; D017442:Histamine Agonists / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000235:genetics; D011738:Pyrilamine / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: D017442:Histamine Agonists; D016328:NF-kappa B; D011969:Receptors, Histamine H1; C118994:histaprodifen; D006632:Histamine; D011738:Pyrilamine