دورية أكاديمية
Systematic N-methylation of oxytocin: Impact on pharmacology and intramolecular hydrogen bonding network.
| العنوان: | Systematic N-methylation of oxytocin: Impact on pharmacology and intramolecular hydrogen bonding network. |
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| المؤلفون: | Sciabola S; Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Neuroscience, 610 Main Street, Cambridge, MA 02139, USA., Goetz GH; Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA., Bai G; Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA., Rogers BN; Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Neuroscience, 610 Main Street, Cambridge, MA 02139, USA., Gray DL; Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Neuroscience, 610 Main Street, Cambridge, MA 02139, USA., Duplantier A; Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Neuroscience, 610 Main Street, Cambridge, MA 02139, USA., Fonseca KR; Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Cambridge, MA 02139, USA., Vanase-Frawley MA; Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA., Kablaoui NM; Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Neuroscience, 610 Main Street, Cambridge, MA 02139, USA. Electronic address: Natasha.M.Kablaoui@pfizer.com. |
| المصدر: | Bioorganic & medicinal chemistry [Bioorg Med Chem] 2016 Aug 15; Vol. 24 (16), pp. 3513-20. Date of Electronic Publication: 2016 May 31. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Elsevier Science Original Publication: Oxford : New York : Pergamon Press, c1993- |
| مواضيع طبية MeSH: | Oxytocin/*chemistry, Hydrogen Bonding ; Magnetic Resonance Spectroscopy ; Methylation ; Structure-Activity Relationship ; Temperature |
| مستخلص: | 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. (Copyright © 2016. Published by Elsevier Ltd.) |
| فهرسة مساهمة: | Keywords: Cyclic peptide; Hidden polarity; Hydrogen bonding; Intramolecular hydrogen bond; NMR; Oxytocin; Peptide; Polarity; SFC |
| المشرفين على المادة: | 50-56-6 (Oxytocin) |
| تواريخ الأحداث: | Date Created: 20160615 Date Completed: 20170802 Latest Revision: 20171207 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1016/j.bmc.2016.05.062 |
| PMID: | 27297999 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1464-3391 |
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| DOI: | 10.1016/j.bmc.2016.05.062 |