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
  • 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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