Synthesis and biological activity of oxytocin analogues containing unnatural amino acids in position 9: structure activity study.
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-beta-(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 beta-mercaptopropionic acid (Mpa) in position 1 modifications in altogether 14 analogues. Additionally, 8 analogues having alpha-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 (beta beta-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 [Mpa(1), D-Tyr(Et)(2), Deg(9)]OT (pA(2) = 8.68 +/- 0.26); this analogue was also selective.
Magafa
Vassiliki
V
Laboratory of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, University of Patras, 26500, Patras, Greece. magafa@upatras.gr
Borovicková
Lenka
L
Slaninová
Jirina
J
Cordopatis
Paul
P
D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D000596:Amino Acids; D010121:Oxytocin