Studying the influence of prolyl amide geometry on bioactivity with 5-t-butylproline oxytocin analogs

Abstract

Prolyl amide geometry can influence the activity of biologically relevant peptides. In the neurohypophyseal hormone oxytocin (OT), the Cys-Pro amide bond joins a 20-member disulfide ring to a three amino acid tail. This prolyl amide exists in an isomeric equilibrium with 10% cis-isomer population in water as observed by NMR spectroscopy [1]. On the contrary, the potent OT bicyclic antagonists [Mpa, cyclo(Glu, Lys)]-OT and [dPen, cyclo(Glu, Lys)]-OT [2, 3, 4] were shown to possess the Cys-Pro amide locked in the cis-isomer conformation. From these observations stems the hypothesis that the prolyl amide cis-isomer may favor antagonism and the trans-isomer is necessary for agonist activity [5]. To explore this hypothesis, we have used steric interactions to augment the cis-isomer population. Three OT analogs were synthesized in which (2S, 5R)-5tbutylproline [6] was substituted for proline in OT, [Mpa]-OT (potent agonist) and [dPen]-OT (potent antagonist).