Send to

Choose Destination
Bioorg Med Chem. 2016 Aug 15;24(16):3513-20. doi: 10.1016/j.bmc.2016.05.062. Epub 2016 May 31.

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

Author information

Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Neuroscience, 610 Main Street, Cambridge, MA 02139, USA.
Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Cambridge, MA 02139, USA.
Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Neuroscience, 610 Main Street, Cambridge, MA 02139, USA. Electronic address:


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.


Cyclic peptide; Hidden polarity; Hydrogen bonding; Intramolecular hydrogen bond; NMR; Oxytocin; Peptide; Polarity; SFC

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center