title: Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure.
abstract: Using rimonabant, a potent inverse agonist for cannabinoid receptor type 1 (CB1R), as parent ligand, a series of novel univalent and bivalent ligands were designed by variation of spacer length and its chemical structure. The ligands synthesized were evaluated for affinity and selectivity by radioligand displacement and a functional steady-state GTPase assay. The results showed the nature of the spacer influences the biological readout. Albeit all compounds show significantly lower affinities than rimonabant, this fact could be used to demonstrate that affinities and selectivity are influenced by the chemical structure and length of the spacer and might be helpful for designing bivalent probes for other GPCR receptors.
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany; Lehrstuhl für Pharmazeutische Chemie I, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Guozheng
authors.initials: G
authors.lastname: Huang
authors.affiliation: Lehrstuhl für Pharmazeutische Biologie, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pemp
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Stadtmüller
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany; Lehrstuhl für Pharmazeutische Chemie I, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Nimczick
authors.affiliation: Lehrstuhl für Pharmazeutische Biologie, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany; Lehrstuhl für Pharmazeutische Biologie, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. Electronic address: michael.decker@uni-wuerzburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000588:Amines; D063386:Cannabinoid Receptor Agonists; D002264:Carboxylic Acids; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1
keywords: Bivalent ligand; CB(1); Cannabinoid receptor; Rimonabant