Synthesis and biological effects of c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012), a new analogue of neurotensin that crosses the blood-brain barrier
Synthesis and biological effects of c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012), a new analogue of neurotensin that crosses the blood-brain barrier
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DOI：
10.1021/jm700925k
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发表时间：
2008-03-27
影响因子：
7.3
通讯作者：
Martinez, Jean
中科院分区：
文献类型：
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作者：
Bredeloux, Pierre;Cavelier, Florine;Martinez, Jean
神经降压素 (NT) 或其 C 端六肽片段 NT(8-13) 的中枢给药在评估急性疼痛的测试中产生强烈的镇痛作用。使用 NT 衍生肽作为药物来缓解患者的剧烈疼痛可能会引起人们的极大兴趣。不幸的是，肽不容易穿透血脑屏障。我们观察到，环状 NT(8-13) 类似物 c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu)（JMV2012，化合物 1）在给小鼠外周给药时产生镇痛和降低体温的作用，表明该肽可穿透血脑屏障并像药物一样有效发挥作用。此外，与相应的单体相比，二聚化合物显示出更高的效力。我们介绍了环状二聚体化合物 1 (JMV2012) 的合成。在小鼠中，即使是外周给药，化合物 1 也会引起严重的低温和有效的镇痛作用。化合物 1 似乎是开发生物活性 NT 类似物作为新型镇痛药物的理想先导化合物。
The central administration of neurotensin (NT) or of its C-terminal hexapeptide fragment NT(8-13), produces strong analgesic effects in tests evaluating acute pain. The use of NT-derived peptides as pharmaceutical agents to relief severe pain in patients could be of great interest. Unfortunately, peptides do not readily penetrate the blood-brain barrier. We have observed that the cyclic NT(8-13) analogue, c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012, compound 1), when peripherally administered to mice produced analgesic and hypothermic effects, suggesting the peptide penetrates the blood-brain barrier and functions effectively like a drug. Moreover, dimeric compounds show increased potency compared to their corresponding monomer. We present the synthesis of the cyclic dimer compound 1 (JMV2012). In mice, compound 1 induced a profound hypothermia and a potent analgesia, even when peripherally administered. Compound 1 appears to be an ideal lead compound for the development of bioactive NT analogues as novel analgesics drugs.