Design and synthesis of delta-opioid receptor selective enkephalin analogues.

Persistent Link:
http://hdl.handle.net/10150/185218
Title:
Design and synthesis of delta-opioid receptor selective enkephalin analogues.
Author:
Gehrig, Catherine Anne.
Issue Date:
1990
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:
A series of conformationally constrained analogues of (D-Pen², D-Pen⁵) enkephalin (DPDPE) was prepared by solid phase peptide synthesis and the opioid activity and selectivity of each analogue was assessed by guinea pig ileum and mouse vas deferens bioassays and rat brain radioreceptor binding assays. For example, the conformationally restricted, cyclic disulfide-containing enkephalin analogue (D-Pen², D-Pen⁵) enkephalin (DPDPE) was modified by addition of a methyl group at either the pro R or pro S position of the beta carbon of the phenylalanine-4 residue and by addition of a nitro group in the para position of the phenylalanine-4 position. Other modifications at the Phe⁴ position included methyl substitution on the aromatic ring and dehydration of the C(α)-Cᵦ bond. In addition the effect of beta, geminal dimethyl groups at position 2 was explored. These peptides demonstrate a wide range of selectivities, some of them being more selective than (DPDPE) for the delta opioid receptor. Two-dimensional NMR experiments have been performed on DPDPE and several of the more interesting analogues to determine their solution conformations. These included the absolute assignments of the Gly³ Cα protons, made possible by the preparation of (D-²H-Gly³) DPDPE. Possible φ backbone dihedral angles and χ₁ side chain rotamer populations were calculated in order to develop a model for the solution conformation in DMSO. These data combined with computer molecular modeling studies (energy minimization and quenched molecular dynamics) using the CHARMM computer programs have helped to elucidate the importance of side chain topography for selectivity at the delta opioid receptor and the conformational properties of the peptide backbone required for binding and transduction.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Chemistry; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Hruby, Victor J.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleDesign and synthesis of delta-opioid receptor selective enkephalin analogues.en_US
dc.creatorGehrig, Catherine Anne.en_US
dc.contributor.authorGehrig, Catherine Anne.en_US
dc.date.issued1990en_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.abstractA series of conformationally constrained analogues of (D-Pen², D-Pen⁵) enkephalin (DPDPE) was prepared by solid phase peptide synthesis and the opioid activity and selectivity of each analogue was assessed by guinea pig ileum and mouse vas deferens bioassays and rat brain radioreceptor binding assays. For example, the conformationally restricted, cyclic disulfide-containing enkephalin analogue (D-Pen², D-Pen⁵) enkephalin (DPDPE) was modified by addition of a methyl group at either the pro R or pro S position of the beta carbon of the phenylalanine-4 residue and by addition of a nitro group in the para position of the phenylalanine-4 position. Other modifications at the Phe⁴ position included methyl substitution on the aromatic ring and dehydration of the C(α)-Cᵦ bond. In addition the effect of beta, geminal dimethyl groups at position 2 was explored. These peptides demonstrate a wide range of selectivities, some of them being more selective than (DPDPE) for the delta opioid receptor. Two-dimensional NMR experiments have been performed on DPDPE and several of the more interesting analogues to determine their solution conformations. These included the absolute assignments of the Gly³ Cα protons, made possible by the preparation of (D-²H-Gly³) DPDPE. Possible φ backbone dihedral angles and χ₁ side chain rotamer populations were calculated in order to develop a model for the solution conformation in DMSO. These data combined with computer molecular modeling studies (energy minimization and quenched molecular dynamics) using the CHARMM computer programs have helped to elucidate the importance of side chain topography for selectivity at the delta opioid receptor and the conformational properties of the peptide backbone required for binding and transduction.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistryen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHruby, Victor J.en_US
dc.contributor.committeememberO'Brien, David F.en_US
dc.contributor.committeememberBurke, Jamesen_US
dc.contributor.committeememberSteelink, Corneliusen_US
dc.contributor.committeememberBurke, Michael F.-
dc.identifier.proquest9108418en_US
dc.identifier.oclc709903594en_US
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