Building bridges for highly selective,potent and stable oxytocin and vasopressin analogs |
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Authors: | Rhiannon Beard Andy Stucki Muriel Schmitt Gabrielle Py Christophe Grundschober Antony D Gee Edward W Tate |
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Institution: | 1. Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK;2. Roche Pharma Research and Early Development, Discovery Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland;3. Division of Imaging Sciences, King’s College London, 4th Floor, Lambeth Wing, St Thomas’ Hospital, SE1 7EH London, UK |
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Abstract: | 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. |
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Keywords: | Oxytocin Disulfide bridging Cyclic peptides Peptide-based drugs Increased stability |
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