Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs

A series of opioid and serotonin re-uptake inhibitors (SSRIs) bifunctional ligands have been designed, synthesized, and tested for their activities and efficacies at mu-, delta- and kappa opioid receptors and SSRIs receptors. Most of the compounds showed high affinities for mu- and delta-opioid receptors and lower affinities for SSRIs and kappa opioid receptors. A docking study on the mu-opioid receptor binding pocket has been carried out for ligands 3-11. The ligands 7 and 11 have displayed the highest binding profiles for the l-opioid receptor binding site with Delta G(bind) (-12.14 kcal/mol) and K-i value (1.0 nM), and Delta G(bind) (-12.41 kcal/mol) and K-i value (0.4 nM), respectively. Ligand 3 was shown to have the potential of dual acting serotonin/norepinephrine re-uptake inhibitor (SNRI) antidepressant activity in addition to opioid activities, and thus could be used for the design of multifunctional ligands in the area of a novel approach for the treatment of pain and depression. (C) 2015 Elsevier Ltd. All rights reserved.