2. Academic Validation
  3. The proof of concept of 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile for the therapy of neuropathic pain

The proof of concept of 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile for the therapy of neuropathic pain

  • Bioorg Chem. 2024 Sep:150:107537. doi: 10.1016/j.bioorg.2024.107537.
José M Entrena 1,  Antonia Artacho-Cordón 2,  Séverine Ravez 3,  Maxime Liberelle 3,  Patricia Melnyk 3,  Mireia Toledano-Pinedo 4,  Pedro Almendros 4,  Enrique J Cobos 5,  José Marco-Contelles 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, and Neurosciences Institute (Biomedical Research Center), University of Granada, Granada, Spain. Electronic address: entrena@ugr.es.
  • 2 Department of Pharmacology, and Neurosciences Institute (Biomedical Research Center), University of Granada, Granada, Spain.
  • 3 University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neurosciences & Cognition, F-59000 Lille, France.
  • 4 Institute of General Organic Chemistry (CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain.
  • 5 Department of Pharmacology, and Neurosciences Institute (Biomedical Research Center), University of Granada, Granada, Spain; Biosanitary Research Institute ibs.GRANADA, Granada, Spain; Teófilo Hernando Institute for Drug Discovery, Madrid, Spain.
  • 6 Institute of General Organic Chemistry (CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, Madrid, Spain. Electronic address: iqoc21@iqog.csic.es.
PMID: 38852313 DOI: 10.1016/j.bioorg.2024.107537
Abstract

In the search for new small molecules for the therapy of neuropathic pain, we found that 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile (12) induced a robust antiallodynic effect in capsaicin-induced mechanical allodynia, a behavioural model of central sensitization, through σ1R antagonism. Furthermore, administration of compound 12 to neuropathic Animals, fully reversed mechanical allodynia, increasing its mechanical threshold to levels that were not significantly different from those found in paclitaxel-vehicle treated mice or from basal levels before neuropathy was induced. Ligand 12 is thus a promising hit-compound for the therapy of neuropathic pain.

Keywords

Functional analysis; Neuropathic pain; Small polyfunctionalized pyridines; σ(1)R.

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