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.