title: Old molecules for new receptors: Trp(Nps) dipeptide derivatives as vanilloid TRPV1 channel blockers.
abstract: The transient receptor potential vanilloid member 1 (TRPV1), an integrator of multiple pain-producing stimuli, is regarded nowadays as an important biological target for the discovery of novel analgesics. Here, we describe the first experimental evidence for the behavior of an old family of analgesic dipeptides, namely Xaa-Trp(Nps) and Trp(Nps)-Xaa (Xaa=Lys, Arg) derivatives, as potent TRPV1 channel blockers. We also report the synthesis and biological investigation of a series of new conformationally restricted Trp(Nps)-dipeptide derivatives with improved TRPV1/NMDA selectivity. Compound 15 b, which incorporates an N-terminal 2S-azetidine-derived Arg residue, was the most selective compound in this series. Collectively, a new family of TRPV1 channel blockers emerged from our results, although further modifications are required to fine-tune the potency/selectivity/toxicity balance.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain.
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Bonache
authors.forename: Carolina
authors.initials: C
authors.lastname: García-Martínez
authors.forename: Laura
authors.initials: L
authors.lastname: García de Diego
authors.forename: Cristina
authors.initials: C
authors.lastname: Carreño
authors.forename: M Jesús
authors.initials: MJ
authors.lastname: Pérez de Vega
authors.forename: M Teresa
authors.initials: MT
authors.lastname: García-López
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.forename: Rosario
authors.initials: R
authors.lastname: González-Muñiz
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D021241:Spectrometry, Mass, Electrospray Ionization; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D004151:Dipeptides; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human