A Cyclic Tetrapeptide ('Cyclodal') and Its Mirror-Image Isomer Are Both High-Affinity mu Opioid Receptor Antagonists

摘要

Head-to-tail cyclization of the mu opioid receptor (MOR) agonist [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2 (9; Dmt = 2',6'-dimethyltyrosine). resulted in a highly active, selective MOR antagonist, c[-D-Are-Phe-Lys-Dmt-] (1) ("cyclodal"), with subnanomolar binding affinity. A docking study Of cyclodal using the crystal structure of MOR in the inactive form showed a unique binding mode with the two basic residues of the ligand forming salt bridges with the Asp(127) and Glu(229) receptor residues. Cyclodal showed high plasma stability and was able to cross the plood, brain barrier to reverse morphine-induced, centrally mediated analgesia when given intravenously. Surprisingly, the mirror-image isomer (optical antipode) of cyclodal, c[-Arg-D-Phe-D-Lys-D-Dmt-] (2), also turned out to be a selective MOR antagonist with 1 nM binding affinity, and thus, these two compounds represent the first example of mirror image opioid receptor ligands with both optical antipodes having high binding affinity. Reduction of the Lys-Dmt peptide bond in cyclodal resulted in an analogue, c[-D-Arg-Phe-Lys Psi[CH2NH]Dmt-] (8) with MOR agonist activity.