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 modelling 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.

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 MARIA. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 59:5(2016), pp. 2179-2191. [10.1021/acs.jmedchem.5b01914]

Tryptamine-based derivatives as Transient Receptor Potential Melastatin type-8 (TRPM8) channel modulators

OSTACOLO, CARMINE
Co-primo
Investigation
;
MUSELLA, SIMONA;NOVELLINO, ETTORE;TAGLIALATELA, MAURIZIO;GOMEZ MONTERREY, ISABEL MARIA
2016

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 modelling 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.
2016
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 MARIA. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 59:5(2016), pp. 2179-2191. [10.1021/acs.jmedchem.5b01914]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/629264
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