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

Abstract

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.

Mapping the Hydrophobic Substrate Binding Site of Phenylalanine Ammonia-Lyase from Petroselinum crispum

“…Unnatural amino acids are valuable building blocks for the pharmaceutical and agrochemical industries. They are also increasingly being incorporated into proteins and peptides. − Phenylalanine analogues have been successfully incorporated into peptidomimetics aimed at addressing the increasing antimicrobial resistance , as well those with antifungal properties and oxytocin analogues …”

The production of l- and d-phenylalanines using engineered phenylalanine ammonia lyases from Petroselinum crispum

“…Substituted phenylalanines are important chiral building blocks for pharmaceutical industry, their incorporation into small-molecule therapeutic agents, or peptides and proteins, is commonly approached 1,2 . Biocatalytic procedures continuously emerged with the aim to provide green alternatives for the production of these valuable synthons.…”

Oxytocin and Its Analogs, Methyl-Substituted in Ortho-, Meta- or Para- Position of Aromatic Ring of Phenylalanine in Position 2: NMR Study and Biological Activities

“…The synthesis and biological qualities of several oxytocin analogues with minor modification in position 2 of the peptide chain are described in the literature [1][2][3][4]. Among these analogues, four are very interesting from the structure activity relationship, (see Scheme 1).…”