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Synthesis, pharmacological evaluation and conformational investigation of endomorphin-2 hybrid analogues

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Abstract

This study reports on new pharmacologically active endomorphin-2 analogues, incorporating β 2-hPhe, β 3-hPhe and β 3-hTic unnatural amino acids in the place of the Phe3–Phe4residues. Such α, β-hybrid analogues were designed to exploit the great potential of β-amino acids in generating conformational variation at the key positions 3 and 4, with the aim of evaluating the effect on the opioid binding affinity. Ligand-stimulated binding assays indicated that some analogues retained a significant affinity, especially for the δ receptor. 1H NMR and molecular modelling suggested the predominance of bent structures for all compounds. The molecular docking with the μ-opioid receptor model was also performed, highlighting a common binding mode for active compounds and helping to rationalize the observed structure–activity data.

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Authors and Affiliations

  1. Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via G, Venezian 21, 20133, Milan, Italy

    Giordano Lesma, Francesco Airaghi, Teresa Recca & Alessandra Silvani

  2. Dipartimento di Scienze Farmaceutiche, Università degliStudi di Ferrara, via Fossato di Mortara 17-19, 44100, Ferrara, Italy

    Severo Salvadori

  3. Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, 6726, Szeged, Hungary

    Engin Bojnik & Anna Borsodi

  4. Dipartimento di Chimica, Materiali ed Ingegneria Chimica‘Giulio Natta’, Politecnico di Milano, via Mancinelli 7, 20131, Milan, Italy

    Alessandro Sacchetti

  5. Dipartimento di Scienze della Vita e dell’Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124, Cagliari, Italy

    Gianfranco Balboni

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  1. Giordano Lesma
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  2. Severo Salvadori
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  3. Francesco Airaghi
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  4. Engin Bojnik
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  5. Anna Borsodi
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  6. Teresa Recca
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  7. Alessandro Sacchetti
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  8. Gianfranco Balboni
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  9. Alessandra Silvani
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Correspondence to Alessandro Sacchetti, Gianfranco Balboni or Alessandra Silvani.

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Lesma, G., Salvadori, S., Airaghi, F. et al. Synthesis, pharmacological evaluation and conformational investigation of endomorphin-2 hybrid analogues. Mol Divers 17, 19–31 (2013). https://doi.org/10.1007/s11030-012-9399-5

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