title: Validation of a histamine H3 receptor model through structure-activity relationships for classical H3 antagonists.
abstract: Histamine H(3) receptor is a G protein-coupled receptor whose activation inhibits the synthesis and release of histamine and other neurotransmitters from nerve endings and is involved in the modulation of different central nervous system functions. H(3) antagonists have been proposed for their potential usefulness in diseases characterized by impaired neurotransmission and they have demonstrated beneficial effects on learning and food intake in animal models. In the present work, a 3D model of the rat histamine H(3) receptor, built by comparative modeling from the crystallographic coordinates of bovine rhodopsin, is presented with the discussion of its ability to predict the potency of known and new H(3) antagonists. A putative binding site for classical, imidazole-derived H(3) antagonists was identified by molecular docking. Comparison with a known pharmacophore model and the binding affinity of a new rigid H(3) antagonist (compound 1, pK(i)=8.02) allowed the characterization of a binding scheme which could also account for the different affinities observed in a recently reported series of potent H(3) antagonists, characterized by a 2-aminobenzimidazole moiety. Molecular dynamics simulations were employed to assess the stability and reliability of the proposed binding mode. Two new conformationally constrained benzimidazole derivatives were prepared and their binding affinity was tested on rat brain membranes; compound 9, designed to reproduce the conformation of a known potent H(3) antagonist, showed higher potency than compound 8, as expected from the binding scheme hypothesized.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43100 Parma, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Lorenzi
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bordi
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.forename: Giovanni
authors.initials: G
authors.lastname: Morini
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects*; D002417:Cattle; D018360:Crystallography, X-Ray; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000145:classification* / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment; D013997:Time Factors
chemical_list: D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; D012243:Rhodopsin