Novel Radiolabeled Vanilloid with Enhanced Specificity for Human Transient Receptor Potential Vanilloid 1 (TRPV1)

Transient receptor potential vanilloid 1 (TRPV1) has emerged as a promising therapeutic target. While radiolabeled resiniferatoxin (RTX) has provided a powerful tool for characterization of vanilloid binding to TRPV1, TRPV1 shows 20-fold weaker binding to the human TRPV1 than to the rodent TRPV1. We...

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Veröffentlicht in:	Journal of medicinal chemistry 2017-10, Vol.60 (19), p.8246-8252
Hauptverfasser:	Pearce, Larry V, Ann, Jihyae, Jung, Aeran, Thorat, Shivaji A, Herold, Brienna K. A, Habtemichael, Amelework D, Blumberg, Peter M, Lee, Jeewoo
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Benzoxazines - chemical synthesis Benzoxazines - pharmacology Binding Sites - drug effects Humans Protein Binding Rats Structure-Activity Relationship Substrate Specificity TRPV Cation Channels - drug effects Urea - analogs & derivatives Urea - chemical synthesis Urea - pharmacology
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Zusammenfassung:	Transient receptor potential vanilloid 1 (TRPV1) has emerged as a promising therapeutic target. While radiolabeled resiniferatoxin (RTX) has provided a powerful tool for characterization of vanilloid binding to TRPV1, TRPV1 shows 20-fold weaker binding to the human TRPV1 than to the rodent TRPV1. We now describe a tritium radiolabeled synthetic vanilloid antagonist, 1-((2-(4-(methyl-[3H])piperidin-1-yl-4-[3H])-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)urea ([3H]MPOU), that embodies improved absolute affinity for human TRPV1 and improved synthetic accessibility.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.7b00859