A Cyclic Tetrapeptide ("Cyclodal") and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists.
Basic Information
ID: ALA3862004
Journal: J Med Chem
Title: A Cyclic Tetrapeptide ("Cyclodal") and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists.
Authors: Weltrowska G, Nguyen TM, Chung NN, Wood J, Ma X, Guo J, Wilkes BC, Ge Y, Laferrière A, Coderre TJ, Schiller PW.
Abstract: Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt1]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2 (9; Dmt = 2',6'-dimethyltyrosine) resulted in a highly active, selective MOR antagonist, c[-d-Arg-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 Asp127 and Glu229 receptor residues. Cyclodal showed high plasma stability and was able to cross the blood-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-LysΨ[CH2NH]Dmt-] (8), with MOR agonist activity.
CiteXplore: 27676089
DOI: 10.1021/acs.jmedchem.6b01200
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