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

P Bredeloux, F Cavelier, I Dubuc, B Vivet… - Journal of medicinal …, 2008 - ACS Publications
P Bredeloux, F Cavelier, I Dubuc, B Vivet, J Costentin, J Martinez
Journal of medicinal chemistry, 2008ACS Publications
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 …
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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