Strategies to target kyotorphin analogues to the brain
Strategies to target kyotorphin analogues to the brain
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DOI：
10.1021/jm970715l
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发表时间：
1998-09-24
影响因子：
7.3
通讯作者：
Prokai, L
中科院分区：
文献类型：
--
作者：
Chen, P;Bodor, N;Prokai, L
本文介绍了一种脑靶向的Kyotorphin类似物（Tyr-Lys）的化学给药系统（CDS）的设计、合成和药理学评价。脑靶向化合物含有包装的伪装形式的活性肽，侧接在C-末端的亲脂性胆固醇酯和1，4-二氢胡芦巴基氧化还原靶向剂之间，通过策略性选择的L-氨基酸间隔基连接到N-末端。发现对于成功的脑靶向，赖氨酸的ε-胺也需要转化为亲脂功能。通过连续的酶促生物活化，Tyr-Lys二肽以持续的方式释放，产生显著和延长的镇痛活性，如大鼠尾潜伏期试验所示。还采用了另一种策略。Lys被氧化还原氨基酸对Nys（+）Nys替代，Nys（+）是Lys的烟酰胺1，4-二氢烟酰胺类似物（Nys（+）是2-氨基-6-（3-氨基甲酰基-1-吡啶鎓基）己酸）。Nys形式是亲脂性的，并且除了C-和N-末端亲脂性功能之外还促进递送。酶促氧化为Nys（+）提供锁定，随后去除亲脂性基团，从脑靶向类似物（BTRA）释放Tyr-Nys（+）。Nys（+）被证明是Arg或Lys的有效替代物。CDS和BTRA的活性分别被纳洛酮拮抗，支持设计的脑靶向过程。最有效的化合物是含有CDS（CDS-PP）的两个脯氨酸间隔区，然后是BTRA。
The design, synthesis, and pharmacological evaluation of brain-targeted chemical delivery systems (CDS) for a kyotorphin analogue (Tyr-Lys) are described. The brain-targeted compound contains the active peptide in a packaged, disguised form, flanked between the lipophilic cholesteryl ester on the C-terminus and the 1,4-dihydrotrigonellyl redox targetor, attached to the N-terminus through strategically selected L-amino acid(s) spacer. It was found that for successful brain targeting, the epsilon-amine of Lys needs to be also converted to a Lipophilic function. Through sequential enzymatic bioactivation, the Tyr-Lys dipeptide is released in a sustained manner, producing significant and prolonged analgesic activity as demonstrated by the rat tail latency test. An alternate strategy was also employed. Lys was replaced by a redox amino acid pair, Nys(+) Nys, the nicotinamide 1,4-dihydronicotinamide analogues of Lys (Nys(+) is 2-amino-6-(3-carbamoyl-1-pyridiniumyl)hexanoic acid). The Nys form is lipophilic and facilitates delivery in addition to the C- and N-terminal lipophilic functions, Enzymatic oxidation to Nys(+) provides the lock-in, followed by removal;of the lipophilic groups, releasing Tyr-Nys(+) from the brain-targeted analogue (BTRA). Nys(+) was shown to be an effective substitution for Arg or Lys. The activities of the CDS and BTRA, respectively,were antagonized by naloxone, supporting the designed brain-targeted processes. The mst potent compound is the two-proline spacer containing CDS (CDS-PP), followed by the BTRA.