title: A chemical switch for the modulation of the functional activity of higher homologues of histamine on the human histamine H3 receptor: effect of various substitutions at the primary amino function.
abstract: In an effort to establish the structural requirements for agonism, neutral antagonism, and inverse agonism at the human histamine H(3) receptor (H(3)R) we have prepared a series of higher homologues of histamine in which the terminal nitrogen of the side chain has been either mono- or disubstituted with several aliphatic, alicyclic, and aromatic moieties or incorporated in cyclic systems. The novel ligands have been pharmacologically investigated in vitro for their affinities on the human H(3)R and H(4)R subtypes by radioligand displacement experiments and for their intrinsic H(3)R activities via a CRE-mediated beta-galactosidase reporter gene assay. Subtle changes of the substitution pattern at the side chain nitrogen alter enormously the pharmacological activity of the ligands, resulting in a series of compounds with a wide spectrum of pharmacological activities. Among the several neutral H(3)R antagonists identified within this series, compounds 2b and 2h display an H(3)R affinity in the low nanomolar concentration range (pK(i) values of 8.1 and 8.4, respectively). A very potent and selective H(3)R agonist (1l, pEC(50) = 8.9, alpha = 0.94) and a very potent, though not highly selective, H(3)R inverse agonist (2k, pIC(50) = 8.9, alpha = -0.97) have been identified as well.
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: Herman D
authors.initials: HD
authors.lastname: Lim
authors.forename: Dris
authors.initials: D
authors.lastname: El-Atmioui
authors.forename: Wiro M P B
authors.initials: WM
authors.lastname: Menge
authors.forename: Henk
authors.initials: H
authors.lastname: Timmerman
authors.forename: Remko A
authors.initials: RA
authors.lastname: Bakker
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: De Esch
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D006632:Histamine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D011968:Receptors, Histamine / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; C418607:HRH4 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D006632:Histamine