Constraining Endomorphin‑1 by β,α-Hybrid Dipeptide/Heterocycle Scaffolds: Identification of a Novel κ‑Opioid Receptor Selective Partial Agonist

Herein
we present the expedient synthesis of endomorphin-1 analogues
containing stereoisomeric β2-homo-Freidinger lactam-like
scaffolds ([Amo2]­EM), and we discuss opioid receptor (OR)
affinity, enzymatic stability, functional activity, in vivo antinociceptive
effects, and conformational and molecular docking analysis. Hence,
H-Tyr-Amo-Trp-PheNH2 resulted to be a new chemotype of
highly stable, selective, partial KOR agonist inducing analgesia,
therefore displaying great potential interest as a painkiller possibly
with reduced harmful side effects.