2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2014 Sep 1;24(17):4209-14. doi: 10.1016/j.bmcl.2014.07.038.
Guozheng Huang 1,  Daniela Pemp 2,  Patricia Stadtmüller 3,  Martin Nimczick 1,  Jörg Heilmann 2,  Michael Decker 4
Affiliations

Affiliations

  • 1 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.
  • 2 Lehrstuhl für Pharmazeutische Biologie, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
  • 3 Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
  • 4 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.
PMID: 25096297 DOI: 10.1016/j.bmcl.2014.07.038
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.

Keywords

Bivalent ligand; CB(1); Cannabinoid receptor; Rimonabant.

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