Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs

Publication date: Available online 12 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Rhiannon Beard, Andy Stucki, Muriel Schmitt, Gabrielle Py, Christophe Grundschober, Antony Gee, Edward Tate
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 (50nM Ki), selectivity (34-fold), and agonist potency (34nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220nM and 69nM, respectively) and pharmacological activity (294nM and 35nM, 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 (14nM 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.

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