113-78-0Relevant articles and documents
Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs
Beard, Rhiannon,Stucki, Andy,Schmitt, Muriel,Py, Gabrielle,Grundschober, Christophe,Gee, Antony D.,Tate, Edward W.
, p. 3039 - 3045 (2018)
Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.
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.
