Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin‑1 (NK1) Antagonist Activities for the Treatment of Pain

Multifunctional ligands with agonist
bioactivities at μ/δ
opioid receptors (MOR/DOR) and antagonist bioactivity at the neurokinin-1
receptor (NK1R) have been designed and synthesized. These peptide-based
ligands are anticipated to produce better biological profiles (e.g.,
higher analgesic effect with significantly less adverse side effects)
compared to those of existing drugs and to deliver better synergistic
effects than coadministration of a mixture of multiple drugs. A systematic
structure–activity relationship (SAR) study has been conducted
to find multifunctional ligands with desired activities at three receptors.
It has been found that introduction of Dmt (2,6-dimethyl-tyrosine)
at the first position and NMePhe at the fourth position
(ligand 3: H-Dmt-d-Ala-Gly-NMePhe-Pro-Leu-Trp-NH-Bn­(3′,5′-(CF3)2)) displays binding as well as functional selectivity for MOR over
DOR while maintaining efficacy, potency, and antagonist activity at
the NK1R. Dmt at the first position with Phe­(4-F)
at the fourth position (ligand 5: H-Dmt-d-Ala-Gly-Phe­(4-F)-Pro-Leu-Trp-NH-Bn­(3′,5′-(CF3)2)) exhibits balanced binding affinities at MOR
and DOR though it has higher agonist activity at DOR over MOR. This
study has led to the discovery of several novel ligands including 3 and 5 with excellent in vitro biological activity
profiles. Metabolic stability studies in rat plasma with ligands 3, 5, and 7 (H-Tyr-d-Ala-Gly-Phe­(4-F)-Pro-Leu-Trp-NH-Bn­(3′,5′-(CF3)2)) showed that their stability depends on modifications
at the first and fourth positions (3: T1/2 > 24 h; 5: T1/2 ≈ 6 h; 7: T1/2 >
2 h). Preliminary in vivo studies with these two ligands have shown
promising antinociceptive activity.