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Title

Synthesis, high-throughput screening and pharmacological characterization of β-lactam derivatives as TRPM8 antagonists

AuthorsTorre-Martínez, Roberto de la; Bonache de Marcos, María Ángeles ; Llabrés-Campaner, P. J.; Balsera, Beatriz; Fernández-Carvajal, Asia; Fernández-Ballester, Gregorio; Pérez de Vega, M. Jesús; González-Muñiz, Rosario
Issue Date2017
PublisherNature Publishing Group
CitationScientific Reports 7 (2017)
AbstractThe mammalian transient receptor potential melastatin channel 8 (TRPM8), highly expressed in trigeminal and dorsal root ganglia, mediates the cooling sensation and plays an important role in the cold hypersensitivity characteristic of some types of neuropathic pain, as well as in cancer. Consequently, the identification of selective and potent ligands for TRPM8 is of great interest. Here, a series of compounds, having a β-lactam central scaffold, were prepared to explore the pharmacophore requirements for TRPM8 modulation. Structure-activity studies indicate that the minimal requirements for potent β-lactam-based TRPM8 blockers are hydrophobic groups (benzyl preferentially or Bu) on R, R, R and R and a short N-alkyl chain (≤3 carbons). The best compounds in the focused library (41 and 45) showed IC values of 46 nM and 83 nM, respectively, in electrophysiology assays. These compounds selectively blocked all modalities of TRPM8 activation, i.e. menthol, voltage, and temperature. Molecular modelling studies using a homology model of TRPM8 identified two putative binding sites, involving networks of hydrophobic interactions, and suggesting a negative allosteric modulation through the stabilization of the closed state. Thus, these β-lactams provide a novel pharmacophore scaffold to evolve TRPM8 allosteric modulators to treat TRPM8 channel dysfunction.
Publisher version (URL)http://dx.doi.org/10.1038/s41598-017-10913-x
URIhttp://hdl.handle.net/10261/157456
DOI10.1038/s41598-017-10913-x
Identifiersdoi: 10.1038/s41598-017-10913-x
issn: 2045-2322
e-issn: 2045-2322
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