Chen P, Bodor N, Wu W M, Prokai L
Center for Drug Discovery, College of Pharmacy, University of Florida, Box 100497 JHMHC, Gainesville, Florida 32610-0497, USA.
J Med Chem. 1998 Sep 24;41(20):3773-81. doi: 10.1021/jm970715l.
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+ left and right arrow Nys, the nicotinamide left and right arrow 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 most potent compound is the two-proline spacer containing CDS (CDS-PP), followed by the BTRA.
描述了一种脑啡肽类似物（Tyr-Lys）的脑靶向化学递送系统（CDS）的设计、合成及药理学评价。该脑靶向化合物以包装、伪装的形式包含活性肽，其两侧分别是C端的亲脂性胆固醇酯和通过策略性选择的L-氨基酸间隔基连接到N端的1,4-二氢胡芦巴碱氧化还原靶向剂。研究发现，为实现成功的脑靶向，赖氨酸的ε-氨基也需要转化为亲脂性功能。通过顺序酶促生物活化，Tyr-Lys二肽以持续的方式释放，如大鼠尾潜伏期试验所示，产生显著且持久的镇痛活性。还采用了另一种策略。赖氨酸被氧化还原氨基酸对Nys+⇄Nys取代，即赖氨酸的烟酰胺⇄1,4-二氢烟酰胺类似物（Nys+为2-氨基-6-(3-氨基甲酰基-1-吡啶鎓基)己酸）。除了C端和N端的亲脂性功能外，Nys形式具有亲脂性并有助于递送。酶促氧化为Nys+提供锁定作用，随后去除亲脂性基团，从脑靶向类似物（BTRA）中释放Tyr-Nys+。已证明Nys+是精氨酸或赖氨酸的有效替代物。CDS和BTRA的活性分别被纳洛酮拮抗，这支持了所设计的脑靶向过程。最有效的化合物是含两个脯氨酸间隔基的CDS（CDS-PP），其次是BTRA。
