Open AccessSynthesis, high-throughput screening and pharmacological characterization of β–lactam derivatives as TRPM8 antagonists
Author(s) -
Rafael Giménez Martínez,
M. Ángeles Bonache,
Pedro J. Llabrés-Campaner,
Beatriz Balsera,
Asia Fernández-Carvajal,
Gregorio FernándezBallester,
Antonio Ferrer-Montiel,
M. Jesús Pérez de Vega,
Rosario GonzálezMuñiz
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-10913-x
Subject(s) - trpm8 , pharmacophore , transient receptor potential channel , chemistry , allosteric regulation , lactam , ion channel , allosteric modulator , trpv1 , stereochemistry , pharmacology , combinatorial chemistry , biophysics , biochemistry , receptor , biology
The 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 t Bu) on R 1 , R 2 , R 3 and R 5 and a short N-alkyl chain (≤3 carbons). The best compounds in the focused library ( 41 and 45 ) showed IC 50 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.