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.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/185218 |
| Date | January 1990 |
| Creators | Gehrig, Catherine Anne. |
| Contributors | Hruby, Victor J., O'Brien, David F., Burke, James, Steelink, Cornelius, Burke, Michael F. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| 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. |
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