Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues.
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.
Gu
Xuyuan
X
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
Ying
Jinfa
J
Min
Byoung
B
Cain
James P
JP
Davis
Peg
P
Willey
Patrick
P
Navratilova
Edita
E
Yamamura
Henry I
HI
Porreca
Frank
F
Hruby
Victor J
VJ
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
D009292:Narcotic Antagonists; D004743:Enkephalin, Leucine