Multivalent ligands with δ/μ opioid agonist and NK1 antagonist activities have shown promising analgesic potency without detectable sign of toxicities, including motor skill impairment and opioid-induced tolerance. To improve their biological activities and metabolic stability, structural optimization was performed on our peptide-derived lead compounds by introducing 2′,6′-dimethyl-l-tyrosine (Dmt) instead of Tyr at the first position. The compound 7 (Dmt-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3′, 5′-(CF3)2-Bzl]) showed improved multivalent bioactivities compared to those of the lead compounds, had more than 6 h half-life in rat plasma, and had significant antinociceptive efficacy in vivo. The NMR structural analysis suggested that Dmt1 incorporation in compound 7 induces the structured conformation in the opioid pharmacophore (N-terminus) and simultaneously shifts the orientation of the NK1 pharmacophore (C-terminus), consistent with its affinities and activities at both opioid and NK1 receptors. These results indicate that compound 7 is a valuable research tool to seek a novel analgesic drug.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Medicinal Chemistry|
|State||Published - Apr 14 2011|
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery