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

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Herein we present the expedient synthesis of endomorphin-1 analogues containing stereoisomeric β 2 -homo-Freidinger lactam-like scaffolds ([Amo 2 ]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-PheNH 2 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.