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

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.