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.

Abstract

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.

• Authors: Pierre Bredeloux, Florine Cavelier, Isabelle Dubuc, Bertrand Vivet, Jean Costentin, Jean Martinez
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 6 Pg. 1610-6 (Mar 27 2008) ISSN: 0022-2623 [Print] United States
• PMID: 18321036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• NTSR2 protein, human
• Oligopeptides
• Peptides, Cyclic
• Receptors, Neurotensin
• cyclo(lysyl-lysyl-prolyl-tyrosyl-isoleucyl-leucyl-lysyl-lysyl-prolyl-tyrosyl-isoleucyl-leucyl)
• neurotensin type 1 receptor
• Neurotensin

Topics

• Amino Acid Sequence
• Analgesia
• Analgesics (chemical synthesis, chemistry, pharmacology)
• Animals
• Blood-Brain Barrier (drug effects)
• Body Temperature (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Hypothermia (chemically induced)
• Injections, Intraperitoneal
• Injections, Intravenous
• Injections, Subcutaneous
• Mice
• Neurotensin (analogs & derivatives, chemical synthesis, pharmacology)
• Oligopeptides (chemical synthesis, chemistry, pharmacology)
• Pain (chemically induced, prevention & control)
• Pain Measurement (drug effects)
• Peptides, Cyclic (administration & dosage, chemical synthesis, chemistry)
• Receptors, Neurotensin (drug effects)