Amino Acids

, Volume 38, Issue 5, pp 1549–1559 | Cite as

Synthesis and biological activity of oxytocin analogues containing unnatural amino acids in position 9: structure activity study

  • Vassiliki Magafa
  • Lenka Borovičková
  • Jiřina Slaninová
  • Paul Cordopatis
Original Article

Abstract

We report the solid phase synthesis and some pharmacological properties of 24 oxytocin (OT) analogues. Basic modifications at position 9 (introduction of l- or d-β-(2-thienyl)-alanine [L- or D-Thi], or l- or d-3-Pyridylalanine [l- or d-3-Pal]) were combined with d-tyrosine(OEthyl) [d-Tyr(Et)] or d-1-naphthylalanine [d-1-Nal] in position 2 and β-mercaptopropionic acid (Mpa) in position 1 modifications in altogether 14 analogues. Additionally, 8 analogues having α-aminoisobutyric acid [Aib] or d-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (d-Tic) or diethylglycine (Deg) in position 9 and d-Tyr(Et) or d-1-Nal or d-Tic in position 2 and Mpa or Pen (ββ-dimethylcysteine) in position 1 were prepared. Two of these analogues have one more modification in position 6, i.e. Pen. Furthermore, two analogues having Mpa in position 1 and d-Tyr(Et) or d-1-Nal in position 2 were prepared for comparison purposes. The analogues were tested for rat uterotonic activity in vitro, in the rat pressor assay and for binding affinity to human OT receptor. The analogue having the highest anti-oxytocic activity was [Mpa1, d-Tyr(Et)2, Deg9]OT (pA2 = 8.68 ± 0.26); this analogue was also selective.

Keywords

Oxytocin antagonists Position 9 Unnatural amino acids Biological activity Binding affinity 

Abbreviations

OT

Oxytocin

Mpa

β-Mercaptopropionic acid

[Mpa1]OT

Deamino-oxytocin

Aib

α-Aminoisobutyric acid

Deg

Diethylglycine

1-Nal

1-Naphthylalanine

3-Pal

3-Pyridylalanine

Pen

ββ-Dimethylcysteine

Thi

β-(2-Thienyl)-alanine

Tic

1,2, 3, 4, -Tetrahydroisoquinoline-3-carboxylic acid

Tyr(Et)

Tyrosine(OEthyl)

Fmoc

9-Fluorenylmethoxycarbonyl

But

t-Butyl

Trt

Trityl

DIC

Diisopropylcarbodiimide

HOBt

1-Hydroxybenzotriazole

DMF

Dimethylformamide

DMSO

Dimethylsulphoxide

TBAF

Tetrabutylammonium fluoride

TFA

Trifluoroacetic acid

HPLC

High-performance liquid chromatography

ESI–MS

Electrospray ionization–mass spectrometry

Notes

Acknowledgments

Partial funding for this work was provided by research project No. Z40550506 of the Academy of Sciences of the Czech Republic.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Vassiliki Magafa
    • 1
  • Lenka Borovičková
    • 2
  • Jiřina Slaninová
    • 2
  • Paul Cordopatis
    • 1
  1. 1.Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of PharmacyUniversity of PatrasPatrasGreece
  2. 2.Department of Antimicrobial Peptides, Institute of Organic Chemistry and BiochemistryAcademy of Sciences of Czech RepublicPrague 6Czech Republic

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