Carbamylation of Amino and Tyrosine Hydroxyl Groups
PREPARATION OF AN INHIBITOR OF OXYTOCIN WITH NO INTRINSIC ACTIVITY ON THE ISOLATED UTERUS
Derek G. Smyth 1
From the
1 From the National Institute for Medical Research, Mill Hill, London, N.W. 7, England
The reactions of cyanate with model compounds containing amino and tyrosine hydroxyl groups have been studied in detail. The reactions involve nucleophilic addition of the amino or phenoxide group to the molecular form of cyanic acid. The proposed mechanism of the reactions has aided in the selection of optimal experimental conditions for the carbamylation of amino and tyrosine hydroxyl groups in proteins and peptides. Carbamylation represents a useful reaction for the reversible blocking of tyrosine hydroxyl groups, the O-carbamyl substituent being readily removed by hydrolysis at neutral and alkaline pH values. By application of the cyanate reaction to oxytocin, two new analogues were obtained, N-carbamyl-O-carbamyloxytocin and N-carbamyloxytocin. The sites of reaction and degree of purity were determined by experiments involving degradation of the molecules and by the use of radioactive labeling. On the isolated uterus, N-carbamyl-O-carbamyloxytocin acts as an inhibitor of oxytocin without itself possessing oxytocic activity; N-carbamyloxytocin is a feebly active analogue with no inhibitory properties. At pH 7.4 and 37°, the inhibitory analogue undergoes slow hydrolysis to yield the weakly active analogue. The very low activity of N-carbamyloxytocin provides an explanation for the inactivation of oxytocin by 8 m urea.
Submitted on March 29, 1966
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