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Potent, Efficacious, and Stable Cyclic Opioid Peptides with Long Lasting Antinociceptive Effect after Peripheral Administration

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posted on 27.12.2019, 20:11 authored by Azzurra Stefanucci, Marilisa Pia Dimmito, Giorgia Macedonio, Laura Ciarlo, Stefano Pieretti, Ettore Novellino, Wei Lei, Deborah Barlow, Karen L. Houseknecht, John M. Streicher, Adriano Mollica
Four novel fluorinated cyclic analogues of biphalin with excellent to modest binding affinity for μ-, δ-, and κ-receptors were synthesized. The cyclic peptides have a combination of piperazine or hydrazine linker with or without a xylene bridge. Among the ligands, MACE3 demonstrated a better activity than biphalin after intravenous administration, and its corresponding analogue incorporating the hydrazine linker (MACE2) was able to induce longer lasting analgesia following subcutaneous administration. An analogue of MACE2 containing 2,6-dimethyl-l-tyrosine (MACE4) showed the best potency and in vivo antinociceptive activity of this series.

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