The Synthesis of 1-(Hemi-homocystine)-oxytocin and A Study of Some of its Pharmacological Properties¹

Converting disulfide bridges in native peptides to stable methylene thioacetals

“…33 Prior investigations into the effect of changing the ring size in native OXT demonstrated a significant decrease in the agonist potency of the ring-adjusted analogue by a factor of up to 500. 34 The macrocyclic ring size modification in oxytocin previously involved the carbon framework of the cysteine residues (homocysteine) and not within the disulfide motif. However, our data suggests that increasing the size of oxytocin's 20-membered ring by insertion of the extra methylene group in between the two sulfur atoms does not significantly reduce its agonist potency.…”

Homocysteine Modification in Protein Structure/Function and Human Disease

“…In one of the variants synthesized, Hcy-oxytocin, Hcy replaces Cys1 (153), which introduces an additional methylene-CH 2 -group and generates a 21-membered disulfide ring, larger than a 20-membered ring of native oxytocin. This structural change causes a loss of pharmacological properties of the hormone: Hcy-oxytocin does not exhibit avian depressor and rat pressor activity and has only Ͻ0.2% of the oxytocic activity of the native oxytocin (153).…”

“…In one of the variants synthesized, Hcy-oxytocin, Hcy replaces Cys1 (153), which introduces an additional methylene-CH 2 -group and generates a 21-membered disulfide ring, larger than a 20-membered ring of native oxytocin. This structural change causes a loss of pharmacological properties of the hormone: Hcy-oxytocin does not exhibit avian depressor and rat pressor activity and has only Ͻ0.2% of the oxytocic activity of the native oxytocin (153). The loss of activity is caused by the increase in size of the ring in Hcy-oxytocin and not by the change in position of the free amino group relative to the disulfide bond, as shown by the synthesis of a deaminated variant of Hcyoxytocin, 1-␥-mercaptobutyric acid-oxytocin, which does not have any avian depressor activity and only 0.8% of oxytocic activity (154).…”

Homocysteine in Protein Structure/Function and Human Disease

“…This shows that Hcy incorporation into protein in place of Met does not lead to breakage of peptide bonds and that Hcy is compatible with protein structure. While Hcy-oxytocin is devoid of biological activity of normal oxytocin [247], AhCV is a substrate for isopenicillin synthase, which oxidizes AhCV to a δ-lactam, a higher homolog of the γ-lactam arising from the oxidation of the natural cysteine-containing precursor [248]. Resulting Hcycontaining peptides are chemically stable.…”

“…One of the analogs prepared is Hcy-oxytocin in which Cys1 residue is replaced by Hcy [247]. This substitution introduces one additional methylene (-CH 2 -) group and generates an analog with a 21-membered disulfide ring, in contrast to oxytocin, which possesses a 20-membered ring.…”