Old molecules for new receptors: Trp(Nps) dipeptide derivatives as vanilloid TRPV1 channel blockers.
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.
Bonache
M Angeles
MA
Instituto de Química Médica (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain.
García-Martínez
Carolina
C
García de Diego
Laura
L
Carreño
Cristina
C
Pérez de Vega
M Jesús
MJ
García-López
M Teresa
MT
Ferrer-Montiel
Antonio
A
González-Muñiz
Rosario
R
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*
D004151:Dipeptides; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human