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Bioorg Med Chem. 2014 Aug 1;22(15):3938-46. doi: 10.1016/j.bmc.2014.06.008. Epub 2014 Jun 13.

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

Author information

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
Lehrstuhl für Pharmazeutische Chemie I, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, 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.

Abstract

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.

KEYWORDS:

Benzimidazole; Bivalent ligand; CB(2); Cannabinoid receptor

PMID:
24984935
DOI:
10.1016/j.bmc.2014.06.008
[Indexed for MEDLINE]

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