Structural and biological exploration of Phe3-Phe 4-modified endomorphin-2 peptidomimetics

Giordano Lesma, Severo Salvadori, Francesco Airaghi, Thomas F. Murray, Teresa Recca, Alessandro Sacchetti, Gianfranco Balboni, Alessandra Silvani

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

This study reports on our ongoing investigation on hybrid EM-2 analogues, in which the great potential of β-amino acids was exploited to generate multiple conformational modifications at the key positions 3 and 4 of the parent peptide. The effect on the opioid binding affinity was evaluated, by means of ligand stimulated binding assays, which indicated a high nanomolar affinity toward the μ-receptor, with appreciable μ/δ selectivity, for some of the new compounds. The three-dimensional properties of the high affinity μ opioid receptor (MOR) ligands were investigated by proton nuclear magnetic resonance, molecular dynamics, and docking studies. In solution, the structures showed extended conformations, which are in agreement with the commonly accepted pharmacophore model for EM-2. From docking studies on an active form of the MOR model, different ligand-receptor interactions have been identified, thus confirming the ability of active compounds to assume a biologically active conformation.

Original languageEnglish (US)
Pages (from-to)795-799
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume4
Issue number8
DOIs
StatePublished - Aug 8 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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    Lesma, G., Salvadori, S., Airaghi, F., Murray, T. F., Recca, T., Sacchetti, A., Balboni, G., & Silvani, A. (2013). Structural and biological exploration of Phe3-Phe 4-modified endomorphin-2 peptidomimetics. ACS Medicinal Chemistry Letters, 4(8), 795-799. https://doi.org/10.1021/ml400189r