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(R)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid is a constrained Phe analogue which can fold into a beta-bend and a helical structure, and to adopt a preferred side-chain disposition in the peptide.
1.Synthesis and biological activity of oxytocin analogues containing conformationally-restricted residues in position 7.
Fragiadaki M;Magafa V;Borovicková L;Slaninová J;Cordopatis P Eur J Med Chem. 2007 Jun;42(6):799-806. Epub 2007 Jan 10.
We report the solid-phase synthesis and some pharmacological properties of twenty oxytocin (OT) analogues. Basic modifications at position 7 (introduction of alpha-aminoisobutyric acid [Aib], L- or D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [L/D-Tic], L-alpha-t-butylglycine [Gly(Bu(t))] and pipecolic acid [Pip]) were combined with D-Tyr(Et)(2), L/D-(pEt)Phe(2), D-Tic(2), and Mpa(1) modifications and their various combinations in a total of 14 analogues. Additionally, two analogues having one more modification in position 3, i.e. Gly(Bu(t)), and three analogues having glycine in position 9 substituted by d-Tic or Aib, were prepared. 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 antioxytocic activity was [Mpa(1), D-Tyr(Et)(2), D-Tic(7), Aib(9)]OT having pA(2)=8.31+/-0.19; this analogue was also selective.
