Synthesis and binding activity of endomorphin-1 analogues containing beta-amino acids

Endomorphin-1 (Tyr-Pro-Trp-PheNH2) has been proposed as the most potent endogenous ligand of the mu-opioid receptors. In this paper, we describe the synthesis of some endomorphin-1 based tetrapeptides in which a residue of the sequence Tyr-Pro-Trp-PheNH2 is replaced by the corresponding beta-isomer. These novel peptides showed different affinities for the opioid receptors labeled with [3H]-DAMGO in rat brain membranes, depending on the beta-amino acid. In particular, the tetrapeptide containing beta-Pro (Tyr-beta-(R)-Pro-Trp-PheNH2) displayed a higher affinity than endogenous endomorphin-1, as revealed by their Ki values (0.33 and 11.1 nM, respectively).