title: Molecular characterization of specific H1-receptor agonists histaprodifen and its Nalpha-substituted analogues on bovine aortic H1-receptors.
abstract: We determined the molecular properties of the selective and potent H(1)-receptor agonist histaprodifen and its N(alpha) substituted analogues: methyl-, dimethyl-, and imidazolylethyl-histaprodifen (suprahistaprodifen). All derivatives show high affinity for (3)H-mepyramine labeled bovine aortic H(1)-receptor binding sites with the following order of potency: suprahistaprodifen > dimethylhistaprodifen > methylhistaprodifen > histaprodifen > histamine. Suprahistaprodifen and dimethylhistaprodifen were the most potent displacers of (3)H-mepyramine binding (K(i)=4.3 and 4.9 nM, respectively). Histaprodifen, methylhistaprodifen and suprahistaprodifen binding was differentially influenced by GTP, whereas dimethylhistaprodifen was not affected. All drugs, except dimethylhistaprodifen, were activators of G-proteins. Their order of potency was suprahistaprodifen > histamine > histaprodifen > methylhistaprodifen. Their effect on G-protein activation was abolished by the addition of the H(1)-receptor antagonist triprolidine (10 microM), which given alone did not activate G-proteins. Our data suggest that histaprodifens are potent but heterogeneous H(1)-receptor ligands with diverse effects on the molecular level in our model system. While the histaprodifen, methylhistaprodifen and suprahistaprodifen data are in agreement with their agonistic nature, as shown in the functional studies performed on different species (rat and guinea pig H(1)-receptor), dimethylhistaprodifen behaved as an antagonist in our study.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia. marija.carman-krzan@mf.uni-lj.si
authors.forename: Marija
authors.initials: M
authors.lastname: Carman-Krzan
authors.forename: Aljosa
authors.initials: A
authors.lastname: Bavec
authors.forename: Matjaz
authors.initials: M
authors.lastname: Zorko
authors.forename: Walter
authors.initials: W
authors.lastname: Schunack
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006632:Histamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017442:Histamine Agonists / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011738:Pyrilamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D020690:GTPase-Activating Proteins; D017442:Histamine Agonists; D011969:Receptors, Histamine H1; C118994:histaprodifen; D014316:Tritium; D006632:Histamine; D019204:GTP-Binding Proteins; D011738:Pyrilamine