Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues
- 19 January 2005
- journal article
- Published by Wiley in Peptide Science
- Vol. 80 (2-3), 151-163
- https://doi.org/10.1002/bip.20208
Abstract
Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid‐phase supports. By taking advantage of the enantioselective synthesis of ω‐unsaturated amino acids and their N‐methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid‐phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2–3 was favored when an L‐ and L‐bicyclic scaffold was used, and that an extended conformation at the N‐terminal was favored when a D‐ and L‐bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]‐ and [7,5]‐bicyclo‐Leu‐enkephalin analogues. © 2005 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2005Keywords
This publication has 44 references indexed in Scilit:
- Conformational preferences of Leu-enkephalin in reverse micelles as membrane-mimicking environmentPeptide Science, 1997
- Site-Selective N-Methylation of Peptides on Solid SupportJournal of the American Chemical Society, 1997
- Identification of a human delta opioid receptor: Cloning and expressionLife Sciences, 1994
- Conformational preferences of [Leu5]enkephalin in biomimetic mediaJBIC Journal of Biological Inorganic Chemistry, 1990
- A crystal molecular conformation of leucine‐enkephalin related to the morphine moleculePeptide Science, 1989
- Crystal structure of an extended-conformation leucine-enkephalin dimer monohydrateLife Sciences, 1987
- Conformational restrictions of biologically active peptides via amino acid side chain groupsLife Sciences, 1982
- Conformational states of enkephalins in solutionBiochemical and Biophysical Research Communications, 1977
- 1H and 13C NMR studies of conformational behaviour of Leu‐enkephalinFEBS Letters, 1977
- Identification of two related pentapeptides from the brain with potent opiate agonist activityNature, 1975