Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 15; pp. 3938 - 3946
• Main Authors: Nimczick, Martin, Pemp, Daniela, Darras, Fouad H., Chen, Xinyu, Heilmann, Jörg, Decker, Michael
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2014
• Subjects: Benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Bivalent ligand; Cannabinoid receptor; CB2; Drug Design; Humans; Kinetics; Ligands; Protein Binding; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism; DMSO; Ag; Ant; CDI; hCB1R; Bivalent ligand; CB2; THF; ECS; Cannabinoid receptor; Benzimidazole; EC50; GPCR; atm; DMF; GTPase; Emax; Ki; hCB2R; CB
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2014.06.008

The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB2R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists.