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

Mehr-Un-Nisa; Munawar A. Munawar; Yeon Sun Lee; David Rankin; Jawaria Munir; Josephine Lai; Misbahul A. Khan; Victor J. Hruby

doi:10.1016/j.bmc.2015.01.047

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

Mehr-Un-Nisa, Munawar A. Munawar, Yeon Sun Lee, David Rankin, Jawaria Munir, Josephine Lai, Misbahul A. Khan, Victor J. Hruby

Chemistry and Biochemistry

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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 ΔG_bind (-12.14 kcal/mol) and K_i value (1.0 nM), and ΔG_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.

Original language	English (US)
Pages (from-to)	1251-1259
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	6
DOIs	https://doi.org/10.1016/j.bmc.2015.01.047
State	Published - Mar 15 2015

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2015.01.047

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Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs. / Mehr-Un-Nisa; Munawar, Munawar A.; Lee, Yeon Sun; Rankin, David; Munir, Jawaria; Lai, Josephine; Khan, Misbahul A.; Hruby, Victor J.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 6, 15.03.2015, p. 1251-1259.

Research output: Contribution to journal › Article › peer-review

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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 (-12.14 kcal/mol) and Ki value (1.0 nM), and ΔGbind (-12.41 kcal/mol) and Ki 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.",

author = "Mehr-Un-Nisa and Munawar, {Munawar A.} and Lee, {Yeon Sun} and David Rankin and Jawaria Munir and Josephine Lai and Khan, {Misbahul A.} and Hruby, {Victor J.}",

note = "Funding Information: We gratefully acknowledge a grant from the Higher Education Commission of Pakistan under the IRSIP program to support Mehr-un-Nisa. This work was partially supported by grants from The U.S. Public Health Services , NIH , and NIDA P01DA006284 and R01DA013449 . Funding Information: K i determinations, receptor binding profiles, agonist and/or antagonist functional data, were generously provided by the National Institute of Mental Health{\textquoteright}s Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

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AU - Mehr-Un-Nisa,

AU - Munawar, Munawar A.

AU - Lee, Yeon Sun

AU - Rankin, David

AU - Munir, Jawaria

AU - Lai, Josephine

AU - Khan, Misbahul A.

AU - Hruby, Victor J.

N1 - Funding Information: We gratefully acknowledge a grant from the Higher Education Commission of Pakistan under the IRSIP program to support Mehr-un-Nisa. This work was partially supported by grants from The U.S. Public Health Services , NIH , and NIDA P01DA006284 and R01DA013449 . Funding Information: K i determinations, receptor binding profiles, agonist and/or antagonist functional data, were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/3/15

Y1 - 2015/3/15

N2 - 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 (-12.14 kcal/mol) and Ki value (1.0 nM), and ΔGbind (-12.41 kcal/mol) and Ki 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.

AB - 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 (-12.14 kcal/mol) and Ki value (1.0 nM), and ΔGbind (-12.41 kcal/mol) and Ki 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.

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

Abstract

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