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 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2008

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

Résumé

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.

Domaines

Chimie organique

Dates et versions

hal-00270388 , version 1 (04-04-2008)

Identifiants

Citer

Pierre Bredeloux, Florine Cavelier, Isabelle Dubuc, Bertrand Vivet, Jean Constantin, et al.. 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. Journal of Medicinal Chemistry, 2008, 51, pp.1610-1616. ⟨10.1021/jm700925k⟩. ⟨hal-00270388⟩
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