Magnesium and biological activity of oxytocin analogues modified on aromatic ring of amino acid in position 2

• Published in: Journal of peptide science Vol. 7; no. 8; pp. 413 - 424
• Main Authors: Slaninova, Jirina, Maletinska, Lenka, Vondrasek, Jiri, Prochazka, Zdenko
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2001
• Subjects: Amino Acid Sequence; Amino Acids - chemistry; aromatic ring; biological activity; Chromatography, Thin Layer; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Ions; magnesium; Magnesium - chemistry; Molecular Sequence Data; Oxytocin - analogs & derivatives; Oxytocin - chemistry; Oxytocin - pharmacology; oxytocin analogues; Peptides - chemistry; Phenylalanine - chemistry; Tyrosine - chemistry
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/psc.334

For the purpose of evaluating substitution effects in the ortho, meta or para positions of the aromatic ring of tyrosine or phenylalanine in position 2 of oxytocin on uterotonic activity in vitro in the presence and absence of magnesium ions, six new analogues of oxytocin ([𝒹‐ and 𝓁‐m‐methylphenylalanine2]oxytocin, [𝒹‐ and 𝓁‐m‐methoxyphenylalanine2]oxytocin and [𝒹‐ and 𝓁‐o‐methyltyrosine2]oxytocin) were synthesized and several previously described analogues resynthesized. For the phenylalanine series, it is found that, in the absence of magnesium ions, substitution of the ortho and meta positions leads to loss of intrinsic activity (the analogues are antagonists) in contrast to the para position. In the tyrosine series, only methyl substitution in the meta position has this effect (substitution of ortho position only attenuates the agonistic biological activity). Addition of Mg ions restores to a certain degree the agonistic activity in the case of the o‐methylphenylalanine analogue and enhances the agonistic activity of o‐methyltyrosine oxytocin. All other analogues keep the original qualities as in the absence of Mg. Molecular modelling calculations of the structure of the above analogues was carried out to help explain these findings of the molecular level. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd.