Jakub Fichna, Jean-Claude do-Rego, Nga N Chung, Carole Lemieux, Peter W Schiller, Jeroen Poels, Jozef Vanden Broeck, Jean Costentin, Anna Janecka
Laboratory of Biomolecular Chemistry, Institute of Biomedicinal Chemistry, Medical University, Lodz, Poland.
Journal of medicinal chemistry 2007 Feb 8To synthesize potent antagonists of the mu-opioid receptor, we prepared a series of endomorphin-1 and endomorphin-2 analogues with 3-(1-naphthyl)-d-alanine (d-1-Nal) or 3-(2-naphthyl)-d-alanine (d-2-Nal) in position 4. Some of these analogues displayed weak antagonist properties. We tried to strengthen these properties by introducing the structurally modified tyrosine residue 2,6-dimethyltyrosine (Dmt) in place of Tyr1. Among the synthesized compounds, [Dmt1, d-2-Nal4]endomorphin-1, designated antanal-1, and [Dmt1, d-2-Nal4]endomorphin-2, designated antanal-2, turned out to be highly potent and selective mu-opioid receptor antagonists, as judged on the basis of two functional assays, the receptor binding assay and the hot plate test of analgesia. Interestingly, another analogue of this series, [Dmt1, d-1-Nal4]endomorphin-1, turned out to be a moderately potent mixed mu-agonist/delta-antagonist.
Jakub Fichna, Jean-Claude do-Rego, Nga N Chung, Carole Lemieux, Peter W Schiller, Jeroen Poels, Jozef Vanden Broeck, Jean Costentin, Anna Janecka. Synthesis and characterization of potent and selective mu-opioid receptor antagonists, [Dmt(1), D-2-Nal(4)]endomorphin-1 (Antanal-1) and [Dmt(1), D-2-Nal(4)]endomorphin-2 (Antanal-2). Journal of medicinal chemistry. 2007 Feb 8;50(3):512-20
PMID: 17266203
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