Structure–Activity Relationships of a Novel Cyclic Hexapeptide That Exhibits Multifunctional Opioid Agonism and Produces Potent Antinociceptive Activity

The
cyclic peptide c[d-Lys2, Asp5]-DN-9
has recently been identified as a multifunctional opioid/neuropeptide
FF receptor agonist, displaying potent analgesic activity with reduced
side effects. This study utilized Tyr-c[d-Lys-Gly-Phe-Asp]-d-Pro-NH2 (0), a cyclic hexapeptide
derived from the opioid pharmacophore of c[d-Lys2, Asp5]-DN-9, as a chemical template. We designed, synthesized,
and characterized 22 analogs of 0 with a single amino
acid substitution to investigate its structure–activity relationship.
Most of these cyclic hexapeptide analogs exhibited multifunctional
activity at μ and δ opioid receptors (MOR and DOR, respectively)
and produced antinociceptive effects following subcutaneous administration.
The lead compound analog 15 showed potent agonistic activities
at the MOR, κ opioid receptor (KOR), and DOR in vitro and produced a strong and long-lasting analgesic effect through
peripheral MOR and KOR in the tail-flick test. Further biological
evaluation identified that analog 15 did not cause significant
side effects such as tolerance, withdrawal, or reward liability.