Synthesis and activity of endomorphin-2 and morphiceptin analogues with proline surrogates in position 2

The opioid agonists endomorphins (Tyr–Pro–Trp–Phe–NH2; EM1 and Tyr–Pro–Phe–Phe–NH2; EM2) and morphiceptin (Tyr–Pro–Phe–Pro–NH2) exhibit an extremely high selectivity for μ-opioid receptor. Here a series of novel EM2 and morphiceptin analogues containing in place of the proline at position 2 the S and R residues of β-homologues of proline (HPro), of 2-pyrrolidinemethanesulphonic acid (HPrs) and of 3-pyrrolidinesulphonic acid (βPrs) have been synthesized and their binding affinity and functional activity have been investigated. The highest μ-receptor affinity is shown by [(S)βPrs2]EM2 analogue (6e) which represents the first example of a β-sulphonamido analogue in the field of opioid peptides.