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Old molecules for new receptors: Trp(Nps) dipeptide derivatives as vanilloid TRPV1 channel blockers
- Source :
- ChemMedChem. 1(4)
- Publication Year :
- 2006
-
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 dipeptldes, namely Xaa-Trp(Nps) and Trp(Nps)-Xaa (Xaa=Lys, Arg) derivatives, as potent TRPV1 channel bolckers. We also report the synthesis and biological investigation of a series of new conformatidnally restricted Trp(Nps)-dipeptide derivatives with improved TRPV1/ NMDA selectivity. Compound 15b, 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.
- Subjects :
- Pharmacology
Spectrometry, Mass, Electrospray Ionization
Dipeptide
Magnetic Resonance Spectroscopy
Peptidomimetic
Stereochemistry
Organic Chemistry
TRPV1
TRPV Cation Channels
Dipeptides
Biochemistry
Recombinant Proteins
Rats
Transient receptor potential channel
chemistry.chemical_compound
chemistry
Biological target
Drug Discovery
Molecular Medicine
NMDA receptor
Animals
Humans
Channel blocker
General Pharmacology, Toxicology and Pharmaceutics
Receptor
Subjects
Details
- ISSN :
- 18607179
- Volume :
- 1
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- ChemMedChem
- Accession number :
- edsair.doi.dedup.....c18a0d7281c690813944089947ee49b8