Synthesis and Pharmacological Evaluation of an Analogue of the Peptide Hormone Oxytocin That Contains a Mimetic of an Inverse γ-Turn

Oxytocin is a neurohypophyseal peptide hormone that induces labor and lactation in mammals. An inverse γ-turn mimetic corresponding to the tripeptide Ile-Val-Asn has been synthesized and incorporated instead of residues 3−5 of oxytocin to probe the hypothesis that a γ-turn involving these residues is found in the receptor bound conformation of oxytocin. In the turn mimetic, residues i and i + 1 are connected by a ψ[CH2O] isostere while a covalent methylene bridge replaces the hydrogen bond that is often found between residues i and i + 2 in γ-turns. The turn mimetic was assembled from three types of building blocks:  an azido epoxide, an α-bromo acid, and a protected β-amino alcohol. The oxytocin analogue did not induce contractions of the uterus nor did it inhibit oxytocin-induced contractions. It is suggested that the loss of bioactivity is mainly due to the presence of a ψ[CH2O] isostere instead of an amide bond between residues i and i + 1 in the turn mimetic.