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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2016 Sep 28

PMID 27676089

Citations 5

Authors

Grazyna Weltrowska

Thi M-D Nguyen

Nga N Chung

JodiAnne Wood

Xiaoyu Ma

Jason Guo

Brian C Wilkes

Yang Ge

Andre Laferriere

Terence J Coderre

Peter W Schiller

Affiliations

Soon will be listed here.

Abstract

Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt]DALDA (H-Dmt-d-Arg-Phe-Lys-NH (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 Asp and Glu 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[CHNH]Dmt-] (8), with MOR agonist activity.

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