title: Synthesis and biological activity of oxytocin analogues containing conformationally-restricted residues in position 7.
abstract: 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.
authors.affiliation: Department of Pharmacy, Laboratory of Pharmacognosy and Chemistry of Natural Products, University of Patras, GR-26500 Patras, Hellas, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Fragiadaki
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Magafa
authors.forename: Lenka
authors.initials: L
authors.lastname: Borovicková
authors.forename: Jirina
authors.initials: J
authors.lastname: Slaninová
authors.forename: Paul
authors.initials: P
authors.lastname: Cordopatis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D006801:Humans; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D018045:Receptors, Oxytocin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D018045:Receptors, Oxytocin; D014667:Vasopressins; D010121:Oxytocin