2. Academic Validation
  3. Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

  • J Med Chem. 2016 Mar 10;59(5):2179-91. doi: 10.1021/acs.jmedchem.5b01914.
Alessia Bertamino 1,  Carmine Ostacolo 2,  Paolo Ambrosino 3,  Simona Musella 2,  Veronica Di Sarno 1,  Tania Ciaglia 1,  Maria Virginia Soldovieri 3,  Nunzio Iraci 1,  Asia Fernandez Carvajal 4,  Roberto de la Torre-Martinez 4,  Antonio Ferrer-Montiel 4,  Rosario Gonzalez Muniz 5,  Ettore Novellino 2,  Maurizio Taglialatela 3,  Pietro Campiglia 1,  Isabel Gomez-Monterrey 2
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno , Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • 2 Department of Pharmacy, University Federico II of Naples , Via D. Montesano 49, 80131, Naples, Italy.
  • 3 Department of Medicine and Health Science V. Tiberio, University of Molise , Via F. de Sanctis, 86100, Campobasso, Italy.
  • 4 Institute of Molecular and Cellular Biology, University Miguel Hernández of Elche , 032020, Elche, Alicante, Spain.
  • 5 Institute of Medicinal Chemistry, IQM-CSIC , c/Juan de la Cierva 3, 28006, Madrid, Spain.
PMID: 26847872 DOI: 10.1021/acs.jmedchem.5b01914
Abstract

Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and Other Diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl)ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl)ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC50 = 40 ± 4 μM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentration-dependent inhibition of menthol-induced TRPM8 currents (IC50 = 367 ± 24 nM). Molecular modeling studies using a homology model of a single rat TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing differences in the binding modes for the agonist and the antagonist.

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