Synthesis and biological evaluation of constrained analogues of the opioid peptide H-Tyr-d-Ala-Phe-Gly-NH2 using the 4-amino-2-benzazepin-3-one scaffold

  1. S. Ballet,
  2. A. Frycia,
  3. J. Piron,
  4. N.N. Chung,
  5. P.W. Schiller,
  6. P. Kosson,
  7. A.W. Lipkowski,
  8. D. Tourwé

Article first published online: 27 SEP 2005

DOI: 10.1111/j.1399-3011.2005.00291.x

Issue

The Journal of Peptide Research

The Journal of Peptide Research

Volume 66, Issue 5, pages 222–230, November 2005

Additional Information

How to Cite

Ballet, S., Frycia, A., Piron, J., Chung, N., Schiller, P., Kosson, P., Lipkowski, A. and Tourwé, D. (2005), Synthesis and biological evaluation of constrained analogues of the opioid peptide H-Tyr-d-Ala-Phe-Gly-NH2 using the 4-amino-2-benzazepin-3-one scaffold. The Journal of Peptide Research, 66: 222–230. doi: 10.1111/j.1399-3011.2005.00291.x

Author Information

  1. S. Ballet, A. Frycia, J. Piron and D. Tourwé Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium N.N. Chung and P.W. Schiller, Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montréal, Montréal, PQ H2W 1R7, Canada P. Kosson and A.W. Lipkowski, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

*D. Tourwé Department of Organic Chemistry Vrije Universiteit Brussel Pleinlaan 2, B-1050 Brussels, Belgium Tel.: 0032-2-6293295 Fax: 0032-2-6293304 E-mail: datourwe@vub.ac.be

Publication History

  1. Issue published online: 5 DEC 2008
  2. Article first published online: 27 SEP 2005
  3. Dates: Received 23 March 2005 Accepted 10 July 2005

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Keywords:

  • 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold;
  • conformational restriction;
  • dermorphin analogues

Abstract:  The synthesis of conformationally restricted dipeptidic moieties 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba)-Gly ([(4S)-amino-3-oxo-1,2,4,5-tetrahydro-1H-2-benzazepin-2-yl]-acetic acid) and 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba)-d-Ala ([(4S)-amino-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-benzo[c]azepin-2-yl]-propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N-acyliminium precursor. Introducing these Aba scaffolds into the N-terminal tetrapeptide of dermorphin (H-Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH2)-induced remarkable shifts in affinity and selectivity towards the opioid μ- and δ-receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N-terminal tetrapeptide H-Tyr-d-Ala-Phe-Gly-NH2, which is the minimal subunit of dermorphin needed for dermorphin-like opiate activity.

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