title: Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists.
abstract: In the present study we searched for neutral antagonists for the human histamine H(1)-receptor (H(1)R) by screening newly synthesized ligands that are structurally related to H(1)R agonists for their affinity using radioligand displacement studies and by assessing their functional activity via performing a NF-kappaB driven reporter-gene assay that allows for the detection of both agonistic and inverse agonistic responses. Starting from the endogenous agonist for the H(1)R, histamine, we synthesized and tested various analogues and ultimately identified several compounds with partial inverse agonistic properties and two neutral H(1)-receptor antagonists, namely 2-[2-(4,4-diphenylbutyl)-1H-imidazol-4-yl]ethylamine (histabudifen, 18d) (pK(i) = 5.8, alpha = 0.02) and 2-[2-(5,5-diphenylpentyl)-1H-imidazol-4-yl]ethylamine (histapendifen, 18e) (pK(i) = 5.9, alpha = -0.09).
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Marinella
authors.initials: M
authors.lastname: Govoni
authors.forename: Remko A
authors.initials: RA
authors.lastname: Bakker
authors.forename: Ineke
authors.initials: I
authors.lastname: van de Wetering
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Wiro M B P
authors.initials: WM
authors.lastname: Menge
authors.forename: Henk
authors.initials: H
authors.lastname: Timmerman
authors.forename: Sigurd
authors.initials: S
authors.lastname: Elz
authors.forename: Walter
authors.initials: W
authors.lastname: Schunack
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002522:Chlorocebus aethiops; D017930:Genes, Reporter; D006632:Histamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D008024:Ligands; D016328:NF-kappa B / Q000235:genetics; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship
chemical_list: C418607:HRH4 protein, human; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D007295:Inositol Phosphates; D008024:Ligands; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C480616:histabudifen; C480617:histapendifen; D006632:Histamine