title: Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues.
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 omega-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.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Xuyuan
authors.initials: X
authors.lastname: Gu
authors.forename: Jinfa
authors.initials: J
authors.lastname: Ying
authors.forename: Byoung
authors.initials: B
authors.lastname: Min
authors.forename: James P
authors.initials: JP
authors.lastname: Cain
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.forename: Patrick
authors.initials: P
authors.lastname: Willey
authors.forename: Edita
authors.initials: E
authors.lastname: Navratilova
authors.forename: Henry I
authors.initials: HI
authors.lastname: Yamamura
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009292:Narcotic Antagonists; D011487:Protein Conformation
chemical_list: D009292:Narcotic Antagonists; D004743:Enkephalin, Leucine