Synthesis, Biological, and Structural Explorations of New Zwitterionic Derivatives of 14‑O‑Methyloxymorphone, as Potent μ/δ Opioid Agonists and Peripherally Selective Antinociceptives

Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14-O-methylmorphinans with natural and unnatural amino acids and three dipeptides at position 6 that emerged as potent μ/δ opioid receptor (MOR/DOR) agonists with peripheral antinoci...

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Veröffentlicht in:Journal of medicinal chemistry 2019-01, Vol.62 (2), p.641-653
Hauptverfasser: Spetea, Mariana, Rief, Silvia B, Haddou, Tanila Ben, Fink, Monika, Kristeva, Elka, Mittendorfer, Harald, Haas, Stefanie, Hummer, Nora, Follia, Valeria, Guerrieri, Elena, Asim, Muhammad Faheem, Sturm, Sonja, Schmidhammer, Helmut
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Sprache:eng
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Zusammenfassung:Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14-O-methylmorphinans with natural and unnatural amino acids and three dipeptides at position 6 that emerged as potent μ/δ opioid receptor (MOR/DOR) agonists with peripheral antinociceptive efficacy is reported. The current study adds significant value to our initial structure–activity relationships on a series of zwitterionic analogues of 1 (14-O-methyloxymorphone) by targeting additional amino acid residues. The new derivatives showed high binding and potent agonism at MOR and DOR in vitro. In vivo, the new 6-amino acid- and 6-dipeptide-substituted derivatives of 1 were highly effective in inducing antinociception in the writhing test in mice after subcutaneous administration, which was antagonized by naloxone methiodide demonstrating activation of peripheral opioid receptors. Such peripheral opioid analgesics may represent alternatives to presently available drugs for a safer pain therapy.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.8b01327