title: 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.affiliation: CNRS FRE 2735, Unité de Neuropsychopharmacologie de la dépression, IFRMP 23, Faculté de Médecine et de Pharmacie, 22 Boulevard Gambetta, Rouen cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bredeloux
authors.forename: Florine
authors.initials: F
authors.lastname: Cavelier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dubuc
authors.forename: Bertrand
authors.initials: B
authors.lastname: Vivet
authors.forename: Jean
authors.initials: J
authors.lastname: Costentin
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
mesh_terms: D000595:Amino Acid Sequence; D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D051379:Mice; D009496:Neurotensin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D018028:Receptors, Neurotensin / Q000187:drug effects
chemical_list: D000700:Analgesics; C490985:NTSR2 protein, human; D009842:Oligopeptides; D010456:Peptides, Cyclic; D018028:Receptors, Neurotensin; C529391:cyclo(lysyl-lysyl-prolyl-tyrosyl-isoleucyl-leucyl-lysyl-lysyl-prolyl-tyrosyl-isoleucyl-leucyl); C114036:neurotensin type 1 receptor; D009496:Neurotensin