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
  • 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.