TY - JOUR
T1 - Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents
AU - Grillo, Alessandro
AU - Fezza, Filomena
AU - Chemi, Giulia
AU - Colangeli, Roberto
AU - Brogi, Simone
AU - Fazio, Domenico
AU - Federico, Stefano
AU - Papa, Alessandro
AU - Relitti, Nicola
AU - Di Maio, Roberto
AU - Giorgi, Gianluca
AU - Lamponi, Stefania
AU - Valoti, Massimo
AU - Gorelli, Beatrice
AU - Saponara, Simona
AU - Benedusi, Mascia
AU - Pecorelli, Alessandra
AU - Minetti, Patrizia
AU - Valacchi, Giuseppe
AU - Butini, Stefania
AU - Campiani, Giuseppe
AU - Gemma, Sandra
AU - Maccarrone, Mauro
AU - Di Giovanni, Giuseppe
PY - 2021/5/5
Y1 - 2021/5/5
N2 - 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.
AB - 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.
KW - Endocannabinoid system
KW - enzyme inhibitors
KW - epilepsy
KW - fatty acid amide hydrolase
KW - seizures
KW - selective inhibitors
KW - temporal lobe epilepsy
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U2 - 10.1021/acschemneuro.1c00192
DO - 10.1021/acschemneuro.1c00192
M3 - Article
C2 - 33890763
AN - SCOPUS:85105969874
VL - 12
SP - 1716
EP - 1736
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 9
ER -