1. Academic Validation
  2. Novel S1R agonists counteracting NMDA excitotoxicity and oxidative stress: A step forward in the discovery of neuroprotective agents

Novel S1R agonists counteracting NMDA excitotoxicity and oxidative stress: A step forward in the discovery of neuroprotective agents

  • Eur J Med Chem. 2023 Mar 5;249:115163. doi: 10.1016/j.ejmech.2023.115163.
Pasquale Linciano 1 Claudia Sorbi 2 Giacomo Rossino 1 Daniela Rossi 1 Andrea Marsala 3 Nunzio Denora 4 Martina Bedeschi 5 Noemi Marino 5 Giacomo Miserocchi 5 Giulio Dondio 6 Marco Peviani 3 Anna Tesei 5 Simona Collina 1 Silvia Franchini 7
Affiliations

Affiliations

  • 1 Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy.
  • 2 Department of Life Sciences, University of Modena and Reggio Emilia, 41125, Modena, Italy.
  • 3 Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100, Pavia, Italy.
  • 4 Dipartimento di Farmacia - Scienze del Farmaco, Università, degli Studi di Bari Aldo Moro, 70126, Bari, Italy.
  • 5 BioScience Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014, Meldola, Italy.
  • 6 Aphad SrL, Via della Resistenza, 65, Buccinasco, 20090, Italy.
  • 7 Department of Life Sciences, University of Modena and Reggio Emilia, 41125, Modena, Italy. Electronic address: silvia.franchini@unimore.it.
Abstract

Sigma-1 receptor (S1R) has been considered a promising therapeutic target for several neurodegenerative diseases and S1R agonists have shown neuroprotective activity against glutamate excitotoxicity and oxidative stress. Starting from a previously identified low nanomolar S1R agonist, in this work we prepared and tested novel benzylpiperidine/benzylpiperazine-based compounds designed by applying a ring opening strategy. Among them, 4-benzyl-1-(2-phenoxyethyl)piperidine 6b (S1R Ki = 0.93 nM) and 4-benzyl-1-(3-phenoxypropyl)piperidine 8b (S1R Ki = 1.1 nM) emerged as high affinity S1R ligands and showed selectivity over S2R and N-methyl-d-aspartate receptor (NMDAR). Candidate compounds behaved as potent S1R agonists being able to enhance the neurite outgrowth induced by nerve growth factor (NGF) in PC12 cell lines. In SH-SY5Y neuroblastoma cell lines they exhibited a neuroprotective effect against rotenone- and NMDA-mediated toxic insults. The neuroprotective activity of 6b and 8b was reverted by co-treatment with an S1R antagonist, PB212. Compounds 6b and 8b were tested for cytotoxicity in-vitro against three human Cancer cell lines (A549, LoVo and Panc-1) and in-vivo zebrafish model, resulting in a good efficacy/safety profile, comparable or superior to the reference drug memantine. Overall, these results encourage further preclinical investigations of 6b and 8b on in-vivo models of neurodegenerative diseases.

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