New paradigm for drug design: Design and synthesis of novel biologically active peptides that are agonists at opioid receptors and antagonists at cholecystokinin receptors

Persistent Link:
http://hdl.handle.net/10150/280340
Title:
New paradigm for drug design: Design and synthesis of novel biologically active peptides that are agonists at opioid receptors and antagonists at cholecystokinin receptors
Author:
Agnes, Richard S
Issue Date:
2003
Publisher:
The University of Arizona.
Rights:
Copyright © 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.
Abstract:
We now know from genomics that many disease states lead to changes in expressed proteins (adaptation/plasticity). Therefore, drug design and discovery based on normal states and single targets often is inadequate or even counter-indicated. Therefore, the "system changes" that have occurred must be considered in any treatment for the disease. Such "systems changes" are clearly evident in neuropathic pain where opioids can actually heighten pain. In these pain states there are increased levels of neurotransmitters such as cholecystokinin (CCK) in which both the peptides and their receptors are increased in pain states. To effectively treat diseases involving "systems changes" a new paradigm for the design of compounds was proposed. In this new approach single peptide or peptidomimetic molecules are designed to interact with multiple receptor targets. For the treatment of pain, a series of linear and cyclic peptides and peptidomimetics were designed based on the overlapping pharmacophores of opioid and CCK ligands. The CCK/opioid analogues were synthesized and evaluated for their biological activities. Several of the CCK/opioid analogues were found to simultaneously interact with opioid receptors as agonists and CCK receptors as antagonists. In addition, the lead compounds have been tested in several pain models and were found to be promising in the treatment of neuropathic pain. Further, the structure-activity relationships of these novel peptides have provided new insights into the requirements for binding and bioactivity at opioid and CCK receptors, as well as the overlapping pharmacophores of CCK and enkephalin.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Pharmaceutical.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Hruby, Victor J.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleNew paradigm for drug design: Design and synthesis of novel biologically active peptides that are agonists at opioid receptors and antagonists at cholecystokinin receptorsen_US
dc.creatorAgnes, Richard Sen_US
dc.contributor.authorAgnes, Richard Sen_US
dc.date.issued2003en_US
dc.publisherThe University of Arizona.en_US
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_US
dc.description.abstractWe now know from genomics that many disease states lead to changes in expressed proteins (adaptation/plasticity). Therefore, drug design and discovery based on normal states and single targets often is inadequate or even counter-indicated. Therefore, the "system changes" that have occurred must be considered in any treatment for the disease. Such "systems changes" are clearly evident in neuropathic pain where opioids can actually heighten pain. In these pain states there are increased levels of neurotransmitters such as cholecystokinin (CCK) in which both the peptides and their receptors are increased in pain states. To effectively treat diseases involving "systems changes" a new paradigm for the design of compounds was proposed. In this new approach single peptide or peptidomimetic molecules are designed to interact with multiple receptor targets. For the treatment of pain, a series of linear and cyclic peptides and peptidomimetics were designed based on the overlapping pharmacophores of opioid and CCK ligands. The CCK/opioid analogues were synthesized and evaluated for their biological activities. Several of the CCK/opioid analogues were found to simultaneously interact with opioid receptors as agonists and CCK receptors as antagonists. In addition, the lead compounds have been tested in several pain models and were found to be promising in the treatment of neuropathic pain. Further, the structure-activity relationships of these novel peptides have provided new insights into the requirements for binding and bioactivity at opioid and CCK receptors, as well as the overlapping pharmacophores of CCK and enkephalin.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Pharmaceutical.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHruby, Victor J.en_US
dc.identifier.proquest3106966en_US
dc.identifier.bibrecord.b44639119en_US
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