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

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posted on 04.02.2016, 00:00 by Alessia Bertamino, Carmine Ostacolo, Paolo Ambrosino, Simona Musella, Veronica Di Sarno, Tania Ciaglia, Maria Virginia Soldovieri, Nunzio Iraci, Asia Fernandez Carvajal, Roberto de la Torre-Martinez, Antonio Ferrer-Montiel, Rosario Gonzalez Muniz, Ettore Novellino, Maurizio Taglialatela, Pietro Campiglia, Isabel Gomez-Monterrey
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.