19063-23-1Relevant articles and documents
Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators
Bertamino, Alessia,Ostacolo, Carmine,Ambrosino, Paolo,Musella, Simona,Di Sarno, Veronica,Ciaglia, Tania,Soldovieri, Maria Virginia,Iraci, Nunzio,Fernandez Carvajal, Asia,De La Torre-Martinez, Roberto,Ferrer-Montiel, Antonio,Gonzalez Muniz, Rosario,Novellino, Ettore,Taglialatela, Maurizio,Campiglia, Pietro,Gomez-Monterrey, Isabel
, p. 2179 - 2191 (2016)
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.
