Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents

Alessandro Grillo, Filomena Fezza, Giulia Chemi, Roberto Colangeli, Simone Brogi, Domenico Fazio, Stefano Federico, Alessandro Papa, Nicola Relitti, Roberto Di Maio, Gianluca Giorgi, Stefania Lamponi, Massimo Valoti, Beatrice Gorelli, Simona Saponara, Mascia Benedusi, Alessandra Pecorelli, Patrizia Minetti, Giuseppe Valacchi, Stefania ButiniGiuseppe Campiani, Sandra Gemma, Mauro Maccarrone, Giuseppe Di Giovanni

Research output: Contribution to journalArticlepeer-review

Abstract

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor 2a. When tested in two rodent models of epilepsy, 2a reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, 2a did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (3a-m). Biological studies highlighted 3h and 3m as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, 3h and 3m could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for 3h (Langendorff perfused rat heart). Finally, the new analogue 3h reduced the severity of the pilocarpine-induced status epilepticus as observed for 2a.

Original languageEnglish
Pages (from-to)1716-1736
Number of pages21
JournalACS Chemical Neuroscience
Volume12
Issue number9
DOIs
Publication statusPublished - May 5 2021

Keywords

  • Endocannabinoid system
  • enzyme inhibitors
  • epilepsy
  • fatty acid amide hydrolase
  • seizures
  • selective inhibitors
  • temporal lobe epilepsy

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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