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@article{Beard:2018:10.1016/j.bmc.2018.03.019,
author = {Beard, R and Stucki, A and Schmitt, M and Py, G and Grundschober, C and Gee, A and Tate, EW},
doi = {10.1016/j.bmc.2018.03.019},
journal = {Bioorganic and Medicinal Chemistry},
pages = {3039--3045},
title = {Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs},
url = {http://dx.doi.org/10.1016/j.bmc.2018.03.019},
volume = {26},
year = {2018}
}
TY - JOUR
AB - 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.
AU - Beard,R
AU - Stucki,A
AU - Schmitt,M
AU - Py,G
AU - Grundschober,C
AU - Gee,A
AU - Tate,EW
DO - 10.1016/j.bmc.2018.03.019
EP - 3045
PY - 2018///
SN - 0968-0896
SP - 3039
TI - Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs
T2 - Bioorganic and Medicinal Chemistry
UR - http://dx.doi.org/10.1016/j.bmc.2018.03.019
UR - http://hdl.handle.net/10044/1/58393
VL - 26
ER -
Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ
e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821