Synthesis, pharmacological evaluation and conformational investigation of endomorphin-2 hybrid analogues

In the last years, a new dimension to the field of biomimetic structures has been introduced,1 through the recognition that the repertoire of polypeptide conformations can be greatly expanded by the creation of structures incorporating β-amino acids.2 Moreover, the numerous advantages of hybrid (mixed α- and β-) backbone peptidomimetics with respect to homogeneous ones were quite recently outlined. We describe here various β-amino acid-based β-hPhe-β-hPhe dipeptide derivatives, also conformationally constrained, and their application to the synthesis and biological evaluation of hybrid analogues of the opioid endogenous peptide endomorphin-2 (EM-2). The opioid system mediates a wide variety of pharmacological and physiological processes, including pain perception and modulation. The amidated tetrapeptide EM-2 has been shown to be μ-opioid receptor (MOR) agonist exhibiting a very high μ-receptor affinity and selectivity, and it is an important model in the search towards new analgesics. Structural investigation of EM-2 reveals the high conformational freedom of the Phe side chains and also the inherent flexibility of the peptide backbone, indicating many probable bioactive conformations, ranging from β- turns to extended conformations. With the aim of better clarify the relevant role of the proper spatial orientation of the aromatic rings and in particular of the benzyl side chains at position 3 and 4, 1H NMR studies, molecular modelling, and molecular docking to a homology MOR model of our hybrid analogues are currently under way.