Four Cyclic Disulfide Pentapeptides Possessing the Ring of Isotocin and Glumitocin

[4-Serine]tocinoic acid and [4-serine]tocinamide (the 20-membered disulfide pentapeptide and pentapeptide amide ring of isotocin and glumitocin), as well as the two deamino analogs [4-serine]deaminotocinoic acid and [4-serine] deaminotocinamide, were synthesized from four protected polypeptide precursors which had been prepared by the stepwise active ester method. All four precursors were prepared from the same intermediate Boc-Tyr(Bzl)-Ile-Ser(Bzl)-Asn-Cys(Bzl)-OBzl (1). For the preparation of the two-ring compounds containing C-terminal amides, 1 was treated with MeOH saturated with NH₃ prior to condensation with either Boc-Cys(Bzl)-ONSu or β-Mpa(Bzl)-ONp. For the preparation of [4-serine]tocinoic acid and [4-serine]deaminotocinoic acid, 1 was condensed with either Z-Cys(Bzl)-ONSu or β-Mpa(Bzl)-ONp. The resulting four protected precursors were then converted to the corresponding ring compounds by deprotection with Na in NH₃, followed by oxidative cyclization. None of the ring compounds showed any significant oxytocic, avian vasodepressor, or rat pressor activity. All showed a slight degree of antioxytocic and antiavian vasodepressor activity but no antipressor activity. Both [4-serine]tocinoic acid and [4-serine]tocinamide showed some milk-ejecting activity.