Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs
Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs
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DOI：
10.1016/j.bmcl.2009.07.061
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发表时间：
2009-09-01
影响因子：
2.7
通讯作者：
Baker, James R., Jr.
中科院分区：
文献类型：
--
作者：
Huang, Baohua;Tang, Shengzhuang;Baker, James R., Jr.
已知缺氧会发生在组织中，作为呼吸抑制的结果，对麻醉性镇痛治疗作出反应。本研究的目的是合成一种麻醉药拮抗剂前体药物，它可以被组织缺氧激活，以防止与呼吸抑制相关的损害。我们利用吲哚醌作为缺氧敏感部分合成了三种不同的麻醉拮抗剂纳洛酮的前药。前药中的吲哚醌结构被设计为在N-1位具有开放的反应点，提供了与大分子进一步缀合以改变这些前药在体内的生物利用度的可能性。纳洛酮和吲哚醌部分通过碳酸酯键连接的前药（标记为1）在磷酸盐缓冲盐水中快速水解。然而，具有氨基甲酸酯接头的两种另外的前药（标记为2和3）在磷酸盐缓冲盐水中稳定24小时。在生物还原酶DT-心肌黄酶存在下，纳洛酮从前药中还原释放，24 h内两种前药的释放率约为80%。超过99%的纳洛酮在30%的人血浆中从前药2释放，然而释放仅发生在缺氧条件下。该系统提供了一种潜在的反馈控制手段，以对抗麻醉性镇痛药引起的严重呼吸抑制。(C)2009爱思唯尔有限公司保留所有权利。
Hypoxia is known to occur in tissues in response to narcotic analgesic therapy using as a result of respiratory depression. The aim of this study was to synthesize a narcotic antagonist pro-drug that can be activated by tissue hypoxia to prevent the damage associated with respiratory depression. We synthesized three different pro-drugs of the narcotic antagonist naloxone utilizing indolequinone as the hypoxia-sensitive moiety. The indolequinone structure in the pro-drugs was designed to have an open reactive point at the N-1 position offering the possibility of further conjugation with macromolecules to modify the bio-availability of these pro-drugs in vivo. A pro-drug (labeled 1) where naloxone and the indolequinone moiety were linked through a carbonate bond was rapidly hydrolyzed in phosphate buffered saline. However, two additional pro-drugs (labeled 2 and 3) having carbamate linkers were stable in phosphate buffered saline for 24 h. The reductive release of naloxone from the pro-drugs was achieved in the presence of the bio-reductive enzyme DT-Diaphorase, with about 80% release occurring from the two pro-drugs in 24 h. More than 99% of naloxone was released from pro-drug 2 in 30% human plasma, however the release only occurred under hypoxic conditions. This system provides a potential means for feedback control to counter critical respiratory depression induced by narcotic analgesics. (C) 2009 Elsevier Ltd. All rights reserved.