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

• Published in: Bioorganic & medicinal chemistry letters 2014-09, Vol.24 (17), p.4209-4214
• Main Authors: Huang, Guozheng, Pemp, Daniela, Stadtmüller, Patricia, Nimczick, Martin, Heilmann, Jörg, Decker, Michael
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Bivalent ligand; Cannabinoid receptor; Cannabinoid Receptor Agonists - chemical synthesis; Cannabinoid Receptor Agonists - chemistry; Cannabinoid Receptor Agonists - pharmacology; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; CB1; Dose-Response Relationship, Drug; Drug Design; Humans; Ligands; Molecular Structure; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - metabolism; Rimonabant; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.07.038

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.