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

AuthorsBertamino, Alessia; Ostacolo, Carmine; Ambrosino, Paolo; Musella, Simona, Di Sarno, Veronica; Ciaglia, Tania; Soldovieri, María Virginia; Iraci, Nunzio; Fernández Carvajal, Asia; Torre-Martínez, Roberto de la; Ferrer-Montiel, Antonio; González Muñiz, María Rosario; Taglialatela, Maurizio; Campiglia, Pietro; Gomez-Monterrey, Isabel; Novellino, Ettore
Issue Date2016
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 59: 2179-2191 (2016)
AbstractPharmacological 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 (EC = 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 (IC = 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.
Description*S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem. 5b01914. Scheme for the synthesis of intermediates 4-phenylbenzyl iodide (III) and 1,2,3,4- tetrahydronaphthalen-4-yl)- methyl 4-methylbenzenesulfonate (IV); SiteMap graphical output for BP1; fittings of the tryptamine-based agonists and antagonists on the respective pharmacophore models; qualitative HPLC runs for derivatives 4− 12 and 14− 22 (PDF) Molecular formula strings (CSV)
Publisher version (URL)http://dx.doi.org/10.1021/acs.jmedchem.5b01914
Identifiersdoi: 10.1021/acs.jmedchem.5b01914
issn: 0022-2623
e-issn: 1520-4804
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