Discovery of a Potent and Efficacious Peptide Derivative for 未/渭 Opioid Agonist/Neurokinin 1 Antagonist Activity with a 2鈥?6鈥?Dimethyl-l-Tyrosine: In vitro, In vivo, and

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• 作者：Takashi Yamamoto ; Padma Nair ; Tally M. Largent-Milnes ; Neil E. Jacobsen ; Peg Davis ; Shou-Wu Ma ; Henry I. Yamamura ; Todd W. Vanderah ; Frank Porreca ; Josephine Lai ; Victor J. Hruby
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2029-2038
• 全文大小：990K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

Multivalent ligands with 未/渭 opioid agonist and NK1 antagonist activities have shown promising analgesic potency without detectable sign of toxicities, including motor skill impairment and opioid-induced tolerance. To improve their biological activities and metabolic stability, structural optimization was performed on our peptide-derived lead compounds by introducing 2鈥?6鈥?dimethyl-l-tyrosine (Dmt) instead of Tyr at the first position. The compound 7 (Dmt-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3鈥?5鈥?(CF₃)₂-Bzl]) showed improved multivalent bioactivities compared to those of the lead compounds, had more than 6 h half-life in rat plasma, and had significant antinociceptive efficacy in vivo. The NMR structural analysis suggested that Dmt¹ incorporation in compound 7 induces the structured conformation in the opioid pharmacophore (N-terminus) and simultaneously shifts the orientation of the NK1 pharmacophore (C-terminus), consistent with its affinities and activities at both opioid and NK1 receptors. These results indicate that compound 7 is a valuable research tool to seek a novel analgesic drug.