Systematic N-methylation of oxytocin: Impact on pharmacology and intramolecular hydrogen bonding network

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• 作者：Simone Sciabola^b ; ^&dagger ; ; Gilles H. Goetz^a ; ^&dagger ; ; Guoyun Bai^a ; ^&dagger ; ; Bruce N. Rogers^b ; David L. Gray^b ; Allen Duplantier^b ; Kari R. Fonseca^c ; Michelle A. Vanase-Frawley^a ; Natasha M. Kablaoui^b ; ^&dagger ; ; ^{Natasha.M.Kablaoui@pfizer.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：SFC ; supercritical fluid chromatography ; Mpa ; mercaptopropionic acid ; SPPS ; solid phase peptide synthesis ; FLIPR ; fluorescent imaging plate reader
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：24
• 期：16
• 页码：3513-3520
• 全文大小：934 K

文摘

Oxytocin (OT) is a peptide hormone agonist of the OT receptor (OTR) that plays an important role in social behaviors such as pair bonding, maternal bonding and trust. The pharmaceutical development of OT as an oral peptide therapeutic has been hindered historically by its unfavorable physicochemical properties, including molecular weight, polarity and number of hydrogen bond donors, which determines poor cell permeability. Here we describe the first systematic study of single and multiple N-methylations of OT and their effect on physicochemical properties as well as potency at the OT receptor. The agonist EC₅₀ and percent effect for OTR are reported and show that most N-methylations are tolerated but with some loss in potency compared to OT. The effect of N-methylation on exposed polarity is assessed through the EPSA chromatographic method and the results validated against NMR temperature coefficient experiments and the determination of NMR solution structures. We found that backbone methylation of residues not involved in IMHB and removal of the N-terminal amine can significantly reduce the exposed polarity of peptides, and yet retain a significant OTR agonist activity. The results of this study also expose the potential challenge of using the N-methylation strategy for the OT system; while exposed polarity is reduced, in some cases backbone methylation produces a significant conformational change that compromises agonist activity. The data presented provides useful insights on the SAR of OT and suggests future design strategies that can be used to develop more permeable OTR agonists based on the OT framework.