RETRO ANALOGS RELATED TO OXYTOCIN

Abstract

[D-alle³]-retro-D-deaminotocinamide (I), retro-L-deaminotocinamide (III) and their respective N-formyl derivatives (II and IV) were synthesized by the stepwise active ester method: deaminotocinamide was prepared by the solid-phase method. The retroanalogs of deaminotocinamide, tested at concentrations up to 10^-5 M, were found to be without activity as agonists or antagonists in the oxytocic assay. At 10^-4 M, [D-alle³]-retro-D-deaminotocinamide is a weak competitive inhibitor of oxytocin. [D-alle³, Gly⁷]-retro-D-deaminooxytocin (V) was synthesized either by the active ester method or by a fragment condensation method employing the retro-D-ring, [D-alle³]-retro-D-deaminotocinamide, and “D-tail”, Boc-Gly-D-Leu-Gly, as the fragments. The N-formyl derivative (VI) of V was prepared by selective N-formylation with p-nitrophenyl formate. Additionally, [D-alle³, Gly⁷, Malonamide⁹]-retro-D-deaminooxytocin (VII) and the model compound [Gly⁷]-retro-L-deaminooxytocin (VIII) were synthesized by the fragment condensation method. In the oxytocic assay, the retro-analogs were found to be neither agonists nor antagonists at concentrations up to 10^-5 M, except for [D-alle³, Gly⁷]-retro-D-deaminooxytocin which showed weak oxytocic activity in the range of 10^-5 to 10^-4 M and may be a partial agonist. It is concluded that the addition of the tripeptide “tail” to the retro-D-ring did not significantly alter the biological activity of the latter, which remains about 10⁵ times lower than that of the active hormone analog [Gly⁷]-oxytocin and about 10⁷ times lower than the hormone itself. The marginal activity of all these retro-D-analogs appears to be directly related to the peptide bond reversal and suggests that the peptide backbone may play an essential role in peptide hormone action.