Dimerization or oligomerization Or many G-protein-coupled receptors (GPCRs), including the cannabinoid I (CBI) receptor, is now widely accepted and may have significant implications for medications development targeting these receptor complexes. A library or bivalent ligands composed or two identical CB1 antagonist pharmacophores derived from SR 141716 linked by spacers of various lengths were developed. The affinities of these bivalent ligands at CB1 and CB2 receptors were determined using radiolabeled binding assays. Their Functional activities were measured using GTP-gamma-S accumulation and intracellular calcium mobilization assays. The results suggest that the nature of the linker and its length are crucial factors for optimurn interactions of these ligands at CB1 receptor binding sites. Finally, selected bivalent ligands (5(1 and 7b) were able to attenuate the antinociceptive erfects of the cannabinoid agonist CP55,940 (21) in a rodent tail-flick assay. These novel compounds may serve as probes that will enable further characterization or CB1 receptor dimerization and oligomerization and its functional significance and may prove useful in the development or new therapeutic approaches to G-protein-coupled receptor mediated disorders
Synthesis and Biological Evaluation of Bivalent Ligands for the Cannabinoid 1 Receptor
Zhang, Y., Gilliam, A., Maitra, R., Damaj, MI., Tajuba, JM., Seltzman, H., & Thomas, B. (2010). Synthesis and Biological Evaluation of Bivalent Ligands for the Cannabinoid 1 Receptor. Journal of Medicinal Chemistry, 53(19), 7048-7060.