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Introduction of a cis-prolyl mimic in position 7 of the peptide hormone oxytocin does not result in antagonistic activity.
Journal article

Introduction of a cis-prolyl mimic in position 7 of the peptide hormone oxytocin does not result in antagonistic activity.

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  • 2005-10-14
Published in:
  • Journal of medicinal chemistry. - 2005
Animals
Binding, Competitive
Blood Pressure
CHO Cells
Cricetinae
Cricetulus
Female
Humans
In Vitro Techniques
Magnetic Resonance Spectroscopy
Male
Molecular Conformation
Molecular Mimicry
Oxytocin
Proline
Radioligand Assay
Rats
Receptors, Oxytocin
Stereoisomerism
Structure-Activity Relationship
Thiazoles
Uterine Contraction
Uterus
English New insights into the structure-activity relationship of the peptide hormone oxytocin are presented. Incorporation of the novel cis-prolyl mimic 2,2-dimethyl-1,3-thiazolidine-4-carboxylic acid (pseudoproline, PsiPro) at position 7 of the hormone yielded the analogue [Cys(Psi(Me,Me)pro)]7oxytocin (1) that showed a 92-95% induction of the cis peptide bond conformation between Cys6 and PsiPro7, as determined by one- and two-dimensional NMR spectra in water and in DMSO-d6. The impact of the dimethyl moiety regarding conformation and bioactivity was investigated by the synthesis of the corresponding dihydro compound, [Cys(Psi(H,H)pro)]7oxytocin (2). Biological tests of the uterotonic activity, the pressor activity, and the binding affinity to the rat and human oxytocin receptors were carried out. As a most significant result, no antagonistic activities were found for both the cis-constrained analogue 1 and analogue 2, suggesting that a cis conformation between residues 6 and 7 of the molecule does not result in antagonistic activity. However, the about 10-fold reduction in agonistic activity of 1 as compared to oxytocin is consistent with the reduction of the trans conformation from 90% for oxytocin to 5-8% for compound 1. Compound 1 retained a high binding affinity for the oxytocin receptor, with K(i) values of 8.0 and 1.9 nM for the rat and the human receptor, respectively. The correlation between the biological activities and the cis contents obtained from NMR analysis for compounds 1, 2, and oxytocin leads to the hypothesis that a cis/trans conformational change plays an important role in oxytocin receptor binding and activation.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/9854
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