Efficient synthesis of norbuprenorphines coupled with enkephalins and investigation of their permeability

Document Type : Research article


1 Peptide Chemistry Research Center, K. N. Toosi University of Technology, 15875-4416, Tehran, Iran.

2 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.

3 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain

4 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain.


An efficient approach for the synthesis of norbuprenorphin derivatives through coupling of enkephalins and norbuprenorphine intermediate is described. Norbuprenorphine derivative was synthesized from thebaine and then, its reaction with succinic acid and phthalic acid was also studied. Meanwhile, the synthesis of enkephalins was done using solid phase peptide synthesis approach. Furthermore, after cleavage of the peptide from the surface of the resin, the coupling of enkephalins with norbuprenorphine derivative was done using TBTU as a coupling reagent then the derivatives were purified using preparative high-pressure liquid chromatography and their structures were confirmed using high-resolution mass spectrometry data. Later, their permeability across membranes was investigated. After PAMPA studies, it was found that the permeability of all norbuprenorphin-enkephalin derivatives was increased, however, succinic and phthalic acid derivatives showed higher permeability than norbuprenorphine-Leu-enkephalin.


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