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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：2179-2191
• 全文大小：707K
• ISSN：1520-4804

文摘

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.