2. Academic Validation
  3. Development of Riluzole Analogs with Improved Use-Dependent Inhibition of Skeletal Muscle Sodium Channels

Development of Riluzole Analogs with Improved Use-Dependent Inhibition of Skeletal Muscle Sodium Channels

  • ACS Med Chem Lett. 2023 Jun 23;14(7):999-1008. doi: 10.1021/acsmedchemlett.3c00224.
Alessandro Farinato 1,  Maria Maddalena Cavalluzzi 2,  Concetta Altamura 3,  Carmen Campanale 3,  Paola Laghetti 3,  Ilaria Saltarella 3,  Pietro Delre 4,  Arthur Barbault 4,  Nancy Tarantino 1,  Gualtiero Milani 2,  Natalie Paola Rotondo 2,  Lorenzo Di Cesare Mannelli 5,  Carla Ghelardini 5,  Sabata Pierno 1,  Giuseppe Felice Mangiatordi 4,  Giovanni Lentini 2,  Jean-François Desaphy 3
Affiliations

Affiliations

  • 1 Section of Pharmacology, Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, 70125 Bari, Italy.
  • 2 Section of Medicinal Chemistry, Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, 70125 Bari, Italy.
  • 3 Section of Pharmacology, Department of Precision and Regenerative Medicine, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.
  • 4 CNR - Institute of Crystallography, via Amendola 122/o, 70126 Bari, Italy.
  • 5 Department NEUROFARBA - Pharmaceutical and Nutraceutical Section, University of Firenze, 50139 Florence, Italy.
PMID: 37465302 DOI: 10.1021/acsmedchemlett.3c00224
Abstract

Several commercially available and newly synthesized riluzole analogs were evaluated in vitro as voltage-gated skeletal muscle sodium-channel blockers. Data obtained from the patch-clamp technique demonstrated that potency is well correlated with lipophilicity and the introduction of a protonatable amino function in the benzothiazole 2-position enhances the use-dependent behavior. The most interesting compound, the 2-piperazine analog of riluzole (14), although slightly less potent than the parent compound in the patch-clamp assay as well as in an in vitro model of myotonia, showed greater use-dependent Nav1.4 blocking activity. Docking studies allowed the identification of the key interactions that 14 makes with the Amino acids of the local anesthetic binding site within the pore of the channel. The reported results pave the way for the identification of novel compounds useful in the treatment of cell excitability disorders.

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