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

Abstract

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.

• Authors: Mehr-un-Nisa, Munawar A Munawar, Yeon Sun Lee, David Rankin, Jawaria Munir, Josephine Lai, Misbahul A Khan, Victor J Hruby
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 6 Pg. 1251-9 (Mar 15 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 25703306 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Ligands
• Receptors, Opioid
• Receptors, Serotonin
• Serotonin Uptake Inhibitors

Topics

• Dose-Response Relationship, Drug
• Drug Design
• Humans
• Ligands
• Molecular Structure
• Receptors, Opioid (metabolism)
• Receptors, Serotonin (metabolism)
• Selective Serotonin Reuptake Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship