Synthesis of stereoisomeric analogues of endomorphin-2, H-Tyr-Pro-Phe-Phe-NH2, and examination of their opioid receptor binding activities and solution conformation

All sixteen stereoisomeric analogues of endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH 2) were synthesized by Fmoc-strategy using solid phase methods. Although sy nthetic endomorphin-2 exhibited similar mu- and delta-opioid receptor-bindi ng activity to the natural compound, endomorphin-2 analogues containing D-a mino acid isomers exhibited lower interaction with mu-receptors depending o n the particular combination. The data clearly indicated that the three dim ensional structure of endomorphin-2 with the natural L-configuration was th e most suitable for binding within the mu receptor, but specific residues a re important for activity. Circular dichroism studies verified that changes in chirality of amino acids in the endomorphin-2 sequence resulted in stru ctural conformation. These alterations significantly reduced the specificit y for mu-receptor-binding sites. (C) 2000 Academic Press.