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Bioorg Med Chem. 2016 Apr 1;24(7):1582-8. doi: 10.1016/j.bmc.2016.02.034. Epub 2016 Feb 26.

Synthesis, biological evaluation and structural analysis of novel peripherally active morphiceptin analogs.

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Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland.
Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland.
Department of Medical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
Institute of Biochemistry, Biological Research Centre of Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6726, Hungary. Electronic address:


Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a tetrapeptide amide, is a selective ligand of the μ-opioid receptor (MOR). This study reports the synthesis and biological evaluation of a series of novel morphiceptin analogs modified in positions 2 or/and 4 by introduction of 4,4-difluoroproline (F2Pro) in l or d configuration. Depending on the fluorinated amino acid configuration and its position in the sequence, new analogs behaved as selective full MOR agonists showing high, moderate, or relatively low potency. The most potent analog, Tyr-F2Pro-Phe-D-F2Pro-NH2, was also able to activate the κ-opioid receptor (KOR), although with low potency. Docking studies and the comparison of results with the high resolution crystallographic structure of a MOR-agonist complex revealed possible structure-activity relationships of this compound family.


Binding studies; Docking; Gastrointestinal transit; Hot-plate test; Molecular dynamics; Opioid receptors; Solid-phase peptide synthesis

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