INHIBITION OF THE ACTION OF OXYTOCIN ON THE RAT UTERUS BY ACYCLIC OXYTOCIN INTERMEDIATES

¹ The Physiology Department, Mount Sinai Medical and Graduate Schools, New York, New York, and The Medical Research Center, Brookhaven National Laboratory, Upton, New York
² The Physiology Department, Mount Sinai Medical and Graduate Schools, New York, New York, and The Medical Research Center, Brookhaven National Laboratory, Upton, New York

A number of C-terminal acyclic peptide intermediates of oxytocin (the tripeptide, L-prolyl-L-leucylglycinamide; the tetrapeptide, S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide; the octapeptide, L-tyrosyI-L-isoleucy-L-glutamnyl-L-asparaginyl-S-benzyl-L-cysteinly-L-prolyl-L-leucylglycinamide, and the hydrobromides of the tetrapeptide, S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide; the pentapeptide, L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide; the hexapeptide, L-glutaminyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamede; and the heptapeptide, L-isoleycyl-L-glutaminyl-L-asparaginyl-S-benzy-L-cysteinyl-L-prolyl-L-leucylcina mide) were synthesized, purified and evaluated for agonistic and antagonistic properties in an in vitro rat uterus assay system. All intermediates were found to be devoid of agonistic activity. However, the tetra- and octapeptide fragments antagonized the uterotonic action of oxytocin. The tetrapeptide proved to be a competitive antagonist of oxytocin activity at low dosage (1-7 x 10^-4 M) with a PA2 of 4.20, but a noncompetitive, reversible inhibitor at high dosage (8-10 x 10^-4 M). The octapeptide proved to be a competitive antagonist with a PA2 of 5.70 throughout the entire dosage range studied (3-36 x 10^-6 M). These observations are discussed in relation to the in vivo degradation of oxytocin and the chemical topographical and chemical functional requirements for inhibitory action of these acycic intermediates of oxytocin.