A Cyclic Tetrapeptide ("Cyclodal") and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists.
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 Asp127and Glu229receptor 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.
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal , 110 Pine Avenue des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
Grazyna
G
Weltrowska
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal , 110 Pine Avenue des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
Thi M-D
TM
Nguyen
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal , 110 Pine Avenue des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
Nga N
NN
Chung
Center for Drug Discovery, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
JodiAnne
J
Wood
Center for Drug Discovery, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
Xiaoyu
X
Ma
Center for Drug Discovery, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
Jason
J
Guo
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal , 110 Pine Avenue des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
Brian C
BC
Wilkes
Anesthesia Research Unit, Department of Anesthesia, McGill University , 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.
Yang
Y
Ge
Anesthesia Research Unit, Department of Anesthesia, McGill University , 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.
André
A
Laferrière
Anesthesia Research Unit, Department of Anesthesia, McGill University , 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.
Terence J
TJ
Coderre
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal , 110 Pine Avenue des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.|Department of Pharmacology, Université de Montréal , Montreal, Quebec H3C 3J7, Canada.
Peter W
PW
Schiller
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D007536:Isomerism; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010456:Peptides, Cyclic; D017450:Receptors, Opioid, mu
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