title: Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists.
abstract: The bioisosteric replacement of the acylguanidine moieties in dimeric histamine H2 receptor (H2R) agonists by carbamoylguanidine groups resulted in compounds with retained potencies and intrinsic activities, but considerably improved stability against hydrolytic cleavage. These compounds achieved up to 2500 times the potency of histamine when studied in [(35)S]GTPγS assays on recombinant human and guinea pig H2R. Unlike 3-(imidazol-4-yl)propyl substituted carbamoylguanidines, the corresponding 2-amino-4-methylthiazoles revealed selectivity over histamine receptor subtypes H1R, H3R and H4R in radioligand competition binding studies. H2R binding studies with three fluorescent compounds and one tritium-labeled ligand, synthesized from a chain-branched precursor, failed due to pronounced cellular accumulation and high non-specific binding. However, the dimeric H2R agonists proved to be useful pharmacological tools for functional studies on native cells, as demonstrated for selected compounds by cAMP accumulation and inhibition of fMLP-stimulated generation of reactive oxygen species in human monocytes.
authors: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Nicole
authors: N
authors: Kagermeier
authors: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str.1, D-30625 Hannover, Germany.
authors: Kristin
authors: K
authors: Werner
authors: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Max
authors: M
authors: Keller
authors: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Paul
authors: P
authors: Baumeister
authors: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Günther
authors: G
authors: Bernhardt
authors: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str.1, D-30625 Hannover, Germany.
authors: Roland
authors: R
authors: Seifert
authors: Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. Electronic address: armin.buschauer@chemie.uni-regensburg.de.
authors: Armin
authors: A
authors: Buschauer
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D005453:Fluorescence; D006146:Guanidines / Q000737:chemistry; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D006146:Guanidines; D017442:Histamine Agonists; D008024:Ligands; D011970:Receptors, Histamine H2; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009240:N-Formylmethionine Leucyl-Phenylalanine
keywords: Bioisosteric replacement; Bivalent ligand; Histamine H(2) receptor; Human monocytes; Receptor subtype selectivity