期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 2, 页码 641-653出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01327
关键词
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资金
- Austrian Science Fund [FWF: P21350, TRP16-B18, TRP19-B18]
- Tyrolean Research Fund [TWF-UNI-0404/949]
- University of Innsbruck
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 mu/delta 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.
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