Arizona Health Sciences

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

TitleDesign, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs.
Publication TypeJournal Article
Year of Publication2015
AuthorsMunawar MA, Lee YSun, Rankin D, Munir J, Lai J, Khan MA, Hruby VJ
JournalBioorg Med Chem
Volume23
Issue6
Pagination1251-9
Date Published2015 Mar 15
ISSN1464-3391
KeywordsDose-Response Relationship, Drug, Drug Design, Humans, Ligands, Molecular Structure, Receptors, Opioid, Receptors, Serotonin, Serotonin Uptake Inhibitors, Structure-Activity Relationship
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.

DOI10.1016/j.bmc.2015.01.047
Alternate JournalBioorg. Med. Chem.
PubMed ID25703306
PubMed Central IDPMC4349363
Grant ListP01 DA006284 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
P01DA006284 / DA / NIDA NIH HHS / United States
R01DA013449 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Yeon Sun Lee, Ph.D.