Advertisement

Stereoselective Synthesis 0f (3S)- and (3R)-3-Hydroxy-3-(2,6-Dimethyl-4-Hydroxyphenyl)Propanoic Acid and its Incorporation into a Cyclic Enkephalin Analogue

  • Grazyna Weltrowska
  • Carole Lemieux
  • Nga N. Chung
  • Brian C. Wilkes
  • Peter W. Schiller
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (volume 611)

Introduction

2',6'-dimethyl substitution of the Tyr1 residue of opioid agonist peptides and deletion of the N-terminal amino group have been shown to represent a general structural modification to convert opioid peptide agonists into antagonists [1]. This conversion required the syntheses of opioid peptide analogues containing 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) in place of Tyr1. The cyclic enkephalin analogue Dhp-c[D-Cys-Gly-Phe(pNO2)-D-Cys]NH2 is a potent μ opioid antagonist and a less potent δ and k antagonist [2]. An analogue of this peptide with β-methylated Dhp, (3S)-3-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(3S)-Mdp], in place of Dhp showed increased antagonist activity at all three receptors, whereas an analogue containing β-isopropyl-substituted Dhp [(3R)-Idp] turned out to be a mixed k agonist/μ antagonist [3]. To further investigate the SAR at the β position of Dhp in the cyclic analogue, we examined the effect of substituting β-hydroxylated...

Keywords

Propanoic Acid Opioid Peptide Aldol Reaction Zinc Dust Stereoselective Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by grants from the CIHR and the NIH.

References

  1. 1.
    Lu, Y., Nguyen, T.M.-D., Weltrowska, G., Berezowska, I., Wilkes, B.C., Lemieux, C, Chung, N.N. and Schiller, P.W. J. Med. Chem. 44, 3048–3053 (2001).CrossRefGoogle Scholar
  2. 2.
    Weltrowska, G., Lu, Y., Lemieux, C, Chung, N.N. and Schiller, P.W. Bioorg. Med. Chem. Lett. 14, 4731–4733 (2004).CrossRefGoogle Scholar
  3. 3.
    Schiller, P.W., Weltrowska, G., Berezowska, I., Lemieux, C, Chung, N.N. and Wilkes, B.C. In Blondelle, S.E., Ed. Understanding Biology Using Peptides (Proceedings of the 19 th American Peptide Symposium), American Peptide Society, San Diego, 2005, pp. 31–35.Google Scholar
  4. 4.
    Evans, D.A., Fitch, D.M., Smith, T.S., Cee, V.J. J. Am. Chem. Soc. 122, 10033–10046 (2000).CrossRefGoogle Scholar
  5. 5.
    Evans, D.A., Britton, D.C. and Ellman, J.A. Tetrahedron Lett. 28, 6141–6144 (1987).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Grazyna Weltrowska
    • 1
  • Carole Lemieux
    • 1
  • Nga N. Chung
    • 1
  • Brian C. Wilkes
    • 1
  • Peter W. Schiller
    • 1
  1. 1.Laboratory of Chemical Biology and Peptide ResearchClinical Research Institute of MontrealMontrealCanada

Personalised recommendations