Design, Synthesis, and Biological Evaluation of Novel Bifunctional C-Terminal-Modified Peptides for /
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- 作者：Takashi Yamamoto ; Padma Nair ; Peg Davis ; Shou-wu Ma ; Edita Navratilova ; Sharif Moye ; Suneeta Tumati ; Josephine Lai ; Todd W. Vanderah ; Henry I. Yamamura ; Frank Porreca ; Victor J. Hruby
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：June 14, 2007
- 年：2007
- 卷：50
- 期：12
- 页码：2779 - 2786
- 全文大小：96K
- 年卷期：v.50,no.12(June 14, 2007)
- ISSN：1520-4804
文摘
A series of bifunctional peptides that act as agonists for 
and 
opioid receptors with selectivity and asantagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application asanalgesics in various pain states. The peptides were characterized using radioligand binding assays andfunctional assays using cell membrane and animal tissue. Optimization was performed on the fifth residuewhich serves as an address moiety for both receptor recognitions. It had critical effects on both activities at/ opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3) 2 (5) and H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF3)2 (7) had excellentagonist activity for both opioid and opioid receptors and excellent antagonist activity for NK1 receptors.These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1antagonist activities can be accomplished and may provide a new tool for treatment of chronic and severalpain states.
and opioid receptors with selectivity and asantagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application asanalgesics in various pain states. The peptides were characterized using radioligand binding assays andfunctional assays using cell membrane and animal tissue. Optimization was performed on the fifth residuewhich serves as an address moiety for both receptor recognitions. It had critical effects on both activities at/ opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3) 2 (5) and H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF3)2 (7) had excellentagonist activity for both opioid and opioid receptors and excellent antagonist activity for NK1 receptors.These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1antagonist activities can be accomplished and may provide a new tool for treatment of chronic and severalpain states.