6663-74-7Relevant articles and documents
A study of the relationship between biological activity and prolyl amide isomer geometry in oxytocin using 5-tert-butylproline to augment the Cys6- Pro7 amide cis-isomer population
Bélec, Laurent,Slaninova, Jirina,Lubell, William D.
, p. 1448 - 1455 (2007/10/03)
Three [5-t-BuPro7]oxytocin analogues were synthesized by substituting (2S,5R)-5-tert-butyl-proline for proline in oxytocin, [Mpa1]oxytocin, and [dPen1]oxytocin. Relative to oxytocin, [5-t-BuPro7]oxytocin and [Mpa1,5-t- BuPro7]oxytocin exhibited strongly reduced binding affinity to the receptor; however, both peptides maintained the pharmacophore characteristics responsible for signal transfer evoking the same maximal response as oxytocin in the single-dose procedure and exhibiting partial agonistic activity in the cumulative dose-response procedure. Although [dPen1]oxytocin exhibited inhibitory as well as partial agonistic activity, [dPen1,5-t- BuPro7]oxytocin exhibited only inhibitory potency with a similar in vitro pA2 value of 7.50 in the absence of magnesium. In the presence of magnesium, [dPen1,5-t-BuPro7]oxytocin exhibited stronger inhibitory potency than [dPen1]oxytocin and no partial agonism. Assignment of the proton signals for the 5-tert-butylprolyl amide cis- and trans-isomers by two-dimensional NMR experiments in water indicated that the Cys6-Pro7 peptide bond cis-isomer population was augmented relative to the prolyl peptides and measured respectively at 35%, 33%, and 20% in the 5-tert-butylproline7 analogues of oxytocin, [Mpa1]oxytocin and [Dpen1]oxytocin. Although caution must be taken when relating the increase in cis-isomer population with an influence on biological activity in [5-t-BuPro7]oxytocin analogues, the synthesis and evaluation of analogues 1-3 have provided additional evidence that can be used to support the hypothesis that the prolyl amide cis-isomer may favor antagonism and the trans-isomer is necessary for agonist activity.
