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

• Published in: Bioorganic & medicinal chemistry 2015-03, Vol.23 (6), p.1251-1259
• Main Authors: Mehr-un-Nisa, Munawar, Munawar A., Lee, Yeon Sun, Rankin, David, Munir, Jawaria, Lai, Josephine, Khan, Misbahul A., Hruby, Victor J.
• Format: Article
• Language: English
• Subjects: Bifunctional ligands; Depression; Dose-Response Relationship, Drug; Drug Design; Humans; Ligands; Molecular Structure; Opioid; Pain; Receptors, Opioid - metabolism; Receptors, Serotonin - metabolism; Serotonin Uptake Inhibitors - chemical synthesis; Serotonin Uptake Inhibitors - chemistry; Serotonin Uptake Inhibitors - pharmacology; SSRIs; Structure-Activity Relationship; Synergistic effect
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.01.047

[Display omitted] A series of opioid and serotonin re-uptake inhibitors (SSRIs) bifunctional ligands have been designed, synthesized, and tested for their activities and efficacies at μ-, δ- and κ opioid receptors and SSRIs receptors. Most of the compounds showed high affinities for μ- and δ-opioid receptors and lower affinities for SSRIs and κ opioid receptors. A docking study on the μ-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 μ-opioid receptor binding site with ΔGbind (−12.14kcal/mol) and Ki value (1.0nM), and ΔGbind (−12.41kcal/mol) and Ki value (0.4nM), 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.