title: 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.affiliation: Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan; Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.lastname: Mehr-un-Nisa
authors.affiliation: Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan.
authors.forename: Munawar A
authors.initials: MA
authors.lastname: Munawar
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA. Electronic address: yeon@email.arizona.edu.
authors.forename: Yeon Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rankin
authors.affiliation: Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan; Institute of Molecular Sciences & Bioinformatics, Lahore 54000, Pakistan.
authors.forename: Jawaria
authors.initials: J
authors.lastname: Munir
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.affiliation: Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan.
authors.forename: Misbahul A
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA. Electronic address: hruby@email.arizona.edu.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011957:Receptors, Opioid / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011957:Receptors, Opioid; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Bifunctional ligands; Depression; Opioid; Pain; SSRIs; Synergistic effect