OXYTOCIN ANALOGS WITH SUBSTITUTIONS IN POSITIONS 3 AND 4.

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Abstract
Synthesis and biological properties are reported for some analogs of oxytocin with replacements of the isoleucine residue in position 3, i.e., [3-proline]oxytocin and [3-d-alanine]oxytocin, and the glutamine residue in position 4, i.e., [4-d-alanine]-oxytocin and [4-d-leucine]oxytocin. [3-Proline]oxytocin exhibited <0.02 U/mg oxytocic activity, 0.005 ± <0.001 U/mg rat pressor activity, and 0.003 ± 0.0001 U/mg antidiuretic activity. [3-d-Alanine]oxytocin had no agonistic activity in the bioassays tested except for the rat antidiuretic assay (<0.0005 U/mg). The 4-d-alanine analog showed 0.05 ± 0.003 U/mg oxytocic activity, 0.07± 0.01 U/mg avian vasodepressor activity, and <0.0001 U/mg rat antidiuretic activity. [4-d-Leucine]oxytocin possessed 0.004 ± <0.001 U/mg rat pressor activity, and showed slight inhibitory properties in the oxytocic and avian vasodepressor assays, inhibiting the oxytocin response in the latter assay by about 60% at a hormone-to-analog ratio of 1:5000. The activity profiles of the analogs are compared to that of oxytocin and are discussed on the basis of the proposed solution conformation of oxytocin.