Topographical design of the message domain pharmacophore of the delta opioid agonists using designer amino acids and design of non-peptide ligand for opioid receptors.
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azu_td_9531085_sip1_m.pdf
Author
Qian, Xinhua.Issue Date
1995Committee Chair
Hruby, Victor J.
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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
A series of highly constrained tyrosine derivatives, 2',6'-dimethyl- β-methyltyrosines (TMTs), was designed and asymmetrically synthesized. Incorporation of the TMT isomers into peptide agonists of δ opioid receptors provide analogues that are highly potent and selectively for δ opioid receptors and have revealed the stereochemical requirements for recognizing opioid δ receptors. Moreover, the combination of conformational studies and pharmacological studies of the peptide analogues provided for the first time the stereochemical requirements for specifically recognizing opioid δ receptor subtypes. The biological active conformation of a highly selective and potent δ opioid agonist, ((2S,3R)-TMT¹) DPDPE, was obtained by NMR studies and computer-assisted modeling. This conformation was then further used for designing novel non-peptide opioid ligands. Thus, this study is another achievement of topographical design of peptide hormones and neurotransmitters. Practically, the results of this study can be used to develop more biological stable pharmaceuticals as strong pain reliever without causing side effects such as physical dependence, respiratory depression, etc.Type
textDissertation-Reproduction (electronic)
Degree Name
Ph.D.Degree Level
doctoralDegree Program
ChemistryGraduate College