title: Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators.
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.
authors: Department of Pharmacy, University of Salerno , Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
authors: Alessia
authors: A
authors: Bertamino
authors: Department of Pharmacy, University Federico II of Naples , Via D. Montesano 49, 80131, Naples, Italy.
authors: Carmine
authors: C
authors: Ostacolo
authors: Department of Medicine and Health Science V. Tiberio, University of Molise , Via F. de Sanctis, 86100, Campobasso, Italy.
authors: Paolo
authors: P
authors: Ambrosino
authors: Department of Pharmacy, University Federico II of Naples , Via D. Montesano 49, 80131, Naples, Italy.
authors: Simona
authors: S
authors: Musella
authors: Department of Pharmacy, University of Salerno , Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
authors: Veronica
authors: V
authors: Di Sarno
authors: Department of Pharmacy, University of Salerno , Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
authors: Tania
authors: T
authors: Ciaglia
authors: Department of Medicine and Health Science V. Tiberio, University of Molise , Via F. de Sanctis, 86100, Campobasso, Italy.
authors: Maria Virginia
authors: MV
authors: Soldovieri
authors: Department of Pharmacy, University of Salerno , Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
authors: Nunzio
authors: N
authors: Iraci
authors: Institute of Molecular and Cellular Biology, University Miguel Hernández of Elche , 032020, Elche, Alicante, Spain.
authors: Asia
authors: A
authors: Fernandez Carvajal
authors: Institute of Molecular and Cellular Biology, University Miguel Hernández of Elche , 032020, Elche, Alicante, Spain.
authors: Roberto
authors: R
authors: de la Torre-Martinez
authors: Institute of Molecular and Cellular Biology, University Miguel Hernández of Elche , 032020, Elche, Alicante, Spain.
authors: Antonio
authors: A
authors: Ferrer-Montiel
authors: Institute of Medicinal Chemistry, IQM-CSIC , c/Juan de la Cierva 3, 28006, Madrid, Spain.
authors: Rosario
authors: R
authors: Gonzalez Muniz
authors: Department of Pharmacy, University Federico II of Naples , Via D. Montesano 49, 80131, Naples, Italy.
authors: Ettore
authors: E
authors: Novellino
authors: Department of Medicine and Health Science V. Tiberio, University of Molise , Via F. de Sanctis, 86100, Campobasso, Italy.
authors: Maurizio
authors: M
authors: Taglialatela
authors: Department of Pharmacy, University of Salerno , Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
authors: Pietro
authors: P
authors: Campiglia
authors: Department of Pharmacy, University Federico II of Naples , Via D. Montesano 49, 80131, Naples, Italy.
authors: Isabel
authors: I
authors: Gomez-Monterrey
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014363:Tryptamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D014363:Tryptamines; C030820:tryptamine