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

被引：42
作者：
Bredeloux, Pierre [3 ]
Cavelier, Florine [1 ,2 ]
Dubuc, Isabelle [3 ]
Vivet, Bertrand [1 ,2 ]
Costentin, Jean [3 ]
Martinez, Jean [1 ,2 ]
机构：
[1] Univ Montpellier 1, CNRS, UMR 5247, IBMM, F-34095 Montpellier, France
[2] Univ Montpellier 2, CNRS, UMR 5247, IBMM, F-34095 Montpellier, France
[3] CNRS, FRE 2735, Unite Neuropsychopharmcol Depress, IFRMP 23,Fac Med & Pharm, F-76183 Rouen, France
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 06期
关键词：
D O I：
10.1021/jm700925k
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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.
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页码：1610 / 1616
页数：7
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