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dc.contributor.advisorHruby, Victor J.en
dc.contributor.authorRamos-Colon, Cyf Nadine
dc.creatorRamos-Colon, Cyf Nadineen
dc.date.accessioned2017-01-04T00:58:25Z
dc.date.available2017-01-04T00:58:25Z
dc.date.issued2016
dc.identifier.urihttp://hdl.handle.net/10150/621869
dc.description.abstractMillions of people in the US currently suffer from chronic pain but available therapeutics do not provide effective chronic pain treatment. Opiate therapy is still the gold standard for chronic pain management with detrimental side effects, such as tolerance, addiction, constipation, and respiratory depression that limit their therapeutic potential. Opiates exert their positive and negative effects by activating the μ opioid receptor (MOR). Conversely, the κ opioid receptor (KOR) has been shown to modulate the tolerance and addiction produced by MOR agonists and is also involved in mood modulation (anxiety and depression). Therefore, blocking KOR activation results in positive effects against opiate side effects and stress-related depression. Dynorphin A (Dyn A) is the endogenous opioid peptide for the KOR. Structure-activity relationship (SAR) studies were carried out to develop a KOR selective antagonist based on the Dyn A structure. A minimum Dyn A pharmacophore with improved stability, no cell toxicity, and antagonist activity was discovered. Peptidomimetic enkephalin analogues previously developed in our group as MOR and δ opioid receptor (DOR) agonists have shown multifunctional activity, with MOR/DOR agonist and KOR antagonist activities. To our knowledge, this finding is first of its class for the opioid receptors. Novel design and synthesis of KOR selective ligands based on our multifunctional enkephalin analogues was done. Successful peptide synthesis resulted in analogues with high stability in rat plasma and no cell toxicity.
dc.language.isoen_USen
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.subject[Des-Arg7] Dynorphin Aen
dc.subjectKappa Opioid Receptor Antagonisten
dc.subjectStructure Activity Relationshipsen
dc.subjectPharmaceutical Sciencesen
dc.subjectChronic Painen
dc.titleDesign, Synthesis, and Biological Evaluation of Novel Peptide Ligands as Kappa Opioid Receptor Antagonistsen_US
dc.typetexten
dc.typeElectronic Dissertationen
thesis.degree.grantorUniversity of Arizonaen
thesis.degree.leveldoctoralen
dc.contributor.committeememberHruby, Victor J.en
dc.contributor.committeememberHulme, Christopheren
dc.contributor.committeememberSun, Daekyuen
dc.contributor.committeememberChapman, Elien
dc.description.releaseRelease after 31-Dec-2021en
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplinePharmaceutical Sciencesen
thesis.degree.namePh.D.en
html.description.abstractMillions of people in the US currently suffer from chronic pain but available therapeutics do not provide effective chronic pain treatment. Opiate therapy is still the gold standard for chronic pain management with detrimental side effects, such as tolerance, addiction, constipation, and respiratory depression that limit their therapeutic potential. Opiates exert their positive and negative effects by activating the μ opioid receptor (MOR). Conversely, the κ opioid receptor (KOR) has been shown to modulate the tolerance and addiction produced by MOR agonists and is also involved in mood modulation (anxiety and depression). Therefore, blocking KOR activation results in positive effects against opiate side effects and stress-related depression. Dynorphin A (Dyn A) is the endogenous opioid peptide for the KOR. Structure-activity relationship (SAR) studies were carried out to develop a KOR selective antagonist based on the Dyn A structure. A minimum Dyn A pharmacophore with improved stability, no cell toxicity, and antagonist activity was discovered. Peptidomimetic enkephalin analogues previously developed in our group as MOR and δ opioid receptor (DOR) agonists have shown multifunctional activity, with MOR/DOR agonist and KOR antagonist activities. To our knowledge, this finding is first of its class for the opioid receptors. Novel design and synthesis of KOR selective ligands based on our multifunctional enkephalin analogues was done. Successful peptide synthesis resulted in analogues with high stability in rat plasma and no cell toxicity.


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