2. Academic Validation
  3. Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity

Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity

  • J Med Chem. 2018 Jul 26;61(14):6140-6152. doi: 10.1021/acs.jmedchem.8b00545.
Alessia Bertamino 1,  Nunzio Iraci 1,  Carmine Ostacolo 2,  Paolo Ambrosino 3,  Simona Musella 2,  Veronica Di Sarno 1,  Tania Ciaglia 1,  Giacomo Pepe 1,  Marina Sala 1,  Maria Virginia Soldovieri 3,  Ilaria Mosca 3,  Sara Gonzalez-Rodriguez 4,  Asia Fernandez-Carvajal 4,  Antonio Ferrer-Montiel 4,  Ettore Novellino 2,  Maurizio Taglialatela 5,  Pietro Campiglia 1,  Isabel Gomez-Monterrey 2
Affiliations

Affiliations

  • 1 Department of Pharmacy , University of Salerno , Via G. Paolo II 132 , 84084 Fisciano , Salerno Italy.
  • 2 Department of Pharmacy , University Federico II of Naples , Via D. Montesano 49 , 80131 Naples , Italy.
  • 3 Department of Medicine and Health Science V. Tiberio , University of Molise , Via F. de Sanctis , 86100 Campobasso , Italy.
  • 4 Institute of Molecular and Cellular Biology , Universitas Miguel Hernández, Avda de la Universidad , 032020 Elche , Spain.
  • 5 Department of Neuroscience, Reproductive Sciences and Dentistry , University Federico II of Naples , Via Pansini, 5 , 80131 Naples , Italy.
PMID: 29939028 DOI: 10.1021/acs.jmedchem.8b00545
Abstract

TRPM8 has been implicated in nociception and pain and is currently regarded as an attractive target for the pharmacological treatment of neuropathic pain syndromes. A series of analogues of N, N'-dibenzyl tryptamine 1, a potent TRPM8 antagonist, was prepared and screened using a fluorescence-based in vitro assay based on menthol-evoked calcium influx in TRPM8 stably transfected HEK293 cells. The tryptophan derivative 14 was identified as a potent (IC50 0.2 ± 0.2 nM) and selective TRPM8 antagonist. In vivo, 14 showed significant target coverage in both an icilin-induced WDS (at 1-30 mg/kg s.c.) and oxaliplatin-induced cold allodynia (at 0.1-1 μg s.c.) mice models. Molecular modeling studies identified the putative binding mode of these antagonists, suggesting that they could influence an interaction network between the S1-4 transmembrane segments and the TRP domains of the channel subunits. The tryptophan moiety provides a new pharmacophoric scaffold for the design of highly potent modulators of TRPM8-mediated pain.

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