The Effects of C-Terminal Modifications on the Opioid Activity of [N-BenzylTyr1]Dynorphin A-(1−11) Analogues
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- 作者：Kshitij A. Patkar ; Thomas F. Murray ; Jane V. Aldrich
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：November 12, 2009
- 年：2009
- 卷：52
- 期：21
- 页码：6814-6821
- 全文大小：872K
- 年卷期：v.52,no.21(November 12, 2009)
- ISSN：1520-4804
文摘
Structural modifications affecting the efficacy of analogues of the endogenous opioid peptide dynorphin (Dyn) A have focused on the N-terminal “message” sequence based on the “message-address” concept. To test the hypothesis that changes in the C-terminal “address” domain could affect efficacy, modified amino acids and cyclic constraints were incorporated into this region of the partial agonist [N-benzylTyr1]Dyn A-(1−11). Modifications in the C-terminal domain of [N-benzylTyr1]Dyn A-(1−11)NH2 resulted in increased κ opioid receptor (KOR) affinity for all of the linear analogues but did not affect the efficacy of these peptides at KOR. Cyclization between positions 5 and 8 yielded [N-benzylTyr1,cyclo(d-Asp5,Dap8)]Dyn A-(1−11)NH2 (zyklophin, 13) (J. Med. Chem. 2005, 48, 4500−4503) with high selectivity for KOR. In contrast to the linear peptides, this peptide exhibits negligible efficacy in the adenylyl cyclase (AC) assay and is a KOR antagonist. These data are consistent with our hypothesis that appropriate modifications in the “address” domain of Dyn A analogues may affect efficacy.