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dc.contributor.advisorHruby, Victor J.en_US
dc.contributor.authorChow, Min-Shine.*
dc.creatorChow, Min-Shine.en_US
dc.date.accessioned2011-10-31T17:31:57Z
dc.date.available2011-10-31T17:31:57Z
dc.date.issued1990en_US
dc.identifier.urihttp://hdl.handle.net/10150/185240
dc.description.abstractSome space-constraining amino acid-containing oxytocin analogues were synthesized, of which the biological activities were found to be remarkably consistent with the predictions based on molecular mechanics calculations using the CHARMM program. Correlations of the biological activities and computer modeling studies of the conformational properties of Tyr², Phe², eBmp² (agonists), Pen¹, and Tic² (antagonists) oxytocin analogs revealed that a g+ conformation for the aromatic ring in the 2-position is important for the oxytocin-uterus receptor transduction. Examination of the topographical features of the energy minimized conformations of these analogs shows that a parallel aromatic surface over the top of the 20-membered disulfide containing ring of the molecule is equally important for the transduction. Though the Tic compound may exclusively exist as the g+ conformation for the aromatic ring in the 2-position, possible backbone changes and particularly the perpendicularly located aromatic ring on the top of the 20-membered ring may be the reason for its antagonism. Calculations shows that (erythro(2S, 3S)-β-methyltyrosine²) OXT has all the requirements for being an highly active compound, while the isomer (threo-L-(2S, 3R)-β-methyltyrosine²) OXT, which differs only in the configuration of the β carbon, is unlikely to be an agonist according to our calculations. Both compounds were synthesized together with other analogs by the solid-phase peptide synthesis techniques on p-methyl-benzhydrylamine resin. The biological activities of these two compounds were consistent with the predictions.
dc.language.isoenen_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.subjectChemistryen_US
dc.titleDesign and synthesis of oxytocin agonists based on molecular mechanics and computer modeling.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.identifier.oclc710218757en_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberHadley, Mac E.en_US
dc.contributor.committeememberSteelink, Corneliusen_US
dc.contributor.committeememberMash, Eugeneen_US
dc.contributor.committeememberBates, Roberten_US
dc.contributor.committeememberCusanovich, Michaelen_US
dc.identifier.proquest9111927en_US
thesis.degree.disciplineChemistryen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.namePh.D.en_US
refterms.dateFOA2018-06-23T05:24:30Z
html.description.abstractSome space-constraining amino acid-containing oxytocin analogues were synthesized, of which the biological activities were found to be remarkably consistent with the predictions based on molecular mechanics calculations using the CHARMM program. Correlations of the biological activities and computer modeling studies of the conformational properties of Tyr², Phe², eBmp² (agonists), Pen¹, and Tic² (antagonists) oxytocin analogs revealed that a g+ conformation for the aromatic ring in the 2-position is important for the oxytocin-uterus receptor transduction. Examination of the topographical features of the energy minimized conformations of these analogs shows that a parallel aromatic surface over the top of the 20-membered disulfide containing ring of the molecule is equally important for the transduction. Though the Tic compound may exclusively exist as the g+ conformation for the aromatic ring in the 2-position, possible backbone changes and particularly the perpendicularly located aromatic ring on the top of the 20-membered ring may be the reason for its antagonism. Calculations shows that (erythro(2S, 3S)-β-methyltyrosine²) OXT has all the requirements for being an highly active compound, while the isomer (threo-L-(2S, 3R)-β-methyltyrosine²) OXT, which differs only in the configuration of the β carbon, is unlikely to be an agonist according to our calculations. Both compounds were synthesized together with other analogs by the solid-phase peptide synthesis techniques on p-methyl-benzhydrylamine resin. The biological activities of these two compounds were consistent with the predictions.


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