Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents

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 <b>2a</b>. When tested in two rodent models of epilepsy, <b>2a</b> reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, <b>2a</b> 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 (<b>3a</b>-<b>m</b>). Biological studies highlighted <b>3h</b> and <b>3m</b> as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, <b>3h</b> and <b>3m</b> could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for <b>3h</b> (Langendorff perfused rat heart). Finally, the new analogue <b>3h</b> reduced the severity of the pilocarpine-induced status epilepticus as observed for <b>2a</b>.