Novel design of bicyclic beta-turn dipeptides on solid-phase supports and synthesis of [3.3.0]-Bicyclo([2,3])-leu-enkephalin analogues.
[structure: see text] External bicyclic beta-turn dipeptide mimetics provide an excellent design approach that can offer a rich chiral ensemble of structures with different backbone conformations. We report herein a novel design of a convergent combinatorial synthetic methodology, which is illustrated by the solid-phase synthesis of a series of [3.3.0]-bicyclo([2,3])-Leu-enkephalin analogues. The reactions were optimized and the epimeric configurations were determined by 2D NMR spectroscopy. Biological assays show that these analogues have more potent delta binding affinity and bioactivity for delta vs micro opioid receptor, which may be related to the different conformations preferred by these analogues in our modeling studies.
Gu
Xuyuan
X
Department of Chemistry, University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, USA.
Ying
Jinfa
J
Agnes
Richard S
RS
Navratilova
Edita
E
Davis
Peg
P
Stahl
Gannon
G
Porreca
Frank
F
Yamamura
Henry I
HI
Hruby
Victor J
VJ
D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013237:Stereoisomerism
D004151:Dipeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D004743:Enkephalin, Leucine