Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents

被引：16

作者：

Grillo, Alessandro ^{[1
]}

Fezza, Filomena ^{[2
]}

Chemi, Giulia ^{[1
]}

Colangeli, Roberto ^{[3
,4
]}

Brogi, Simone ^{[5
]}

Fazio, Domenico ^{[6
]}

Federico, Stefano ^{[1
]}

Papa, Alessandro ^{[1
]}

Relitti, Nicola ^{[1
]}

Di Maio, Roberto ^{[7
,8
]}

Giorgi, Gianluca ^{[1
]}

Lamponi, Stefania ^{[1
]}

Valoti, Massimo ^{[9
]}

Gorelli, Beatrice ^{[9
]}

Saponara, Simona ^{[9
]}

Benedusi, Mascia ^{[10
]}

Pecorelli, Alessandra ^{[11
]}

Minetti, Patrizia ^{[12
]}

Valacchi, Giuseppe ^{[10
,11
,13
]}

Butini, Stefania ^{[1
]}

Campiani, Giuseppe ^{[1
]}

Gemma, Sandra ^{[1
]}

Maccarrone, Mauro ^{[6
,14
]}

Di Giovanni, Giuseppe ^{[3
,15
]}

机构：

[1] Univ Siena, Dept Excellence Biotechnol Chem & Pharm, I-53100 Siena, Italy

[2] Univ Rome, Dept Expt Med Tor Vergata, I-00121 Rome, Italy

[3] Univ Malta, Fac Med & Surg, Dept Physiol & Biochem, Lab Neurophysiol, MSD-2080 Msida, Malta

[4] Univ Politecn Marche, Dept Expt & Clin Med, Sect Neurosci & Cell Biol, I-60126 Ancona, Italy

[5] Univ Pisa, Dept Pharm, I-56126 Pisa, Italy

[6] IRCCS Santa Lucia Fdn, European Ctr Brain Res, I-00143 Rome, Italy

[7] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15261 USA

[8] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15261 USA

[9] Univ Siena, Dept Life Sci, I-53100 Siena, Italy

[10] Univ Ferrara, Dept Biomed & Specialist Surg Sci, Sect Med Biochem Mol Biol & Genet, I-44121 Ferrara, Italy

[11] NC State Univ, Plants Human Hlth Inst, Dept Anim Sci, NC Res Campus, Kannapolis, NC 28081 USA

[12] Sigma Tau Pharmaceut Co, I-400 Pomezia, Italy

[13] Kyung Hee Univ, Dept Food & Nutr, Seoul 02447, South Korea

[14] Univ Aquila, Dept Biotechnol & Appl Clin Sci, I-67100 Laquila, Italy

[15] Cardiff Univ, Sch Biosci, Neurosci Div, Cardiff CF10 3AT, Wales

来源：

ACS CHEMICAL NEUROSCIENCE | 2021年 / 12卷 / 09期

关键词：

Endocannabinoid system; fatty acid amide hydrolase; enzyme inhibitors; selective inhibitors; epilepsy; temporal lobe epilepsy; seizures; MEDICALLY INTRACTABLE EPILEPSY; MAXIMAL DENTATE ACTIVATION; INDUCED STATUS EPILEPTICUS; ENDOCANNABINOID SYSTEM; CB1; RECEPTOR; CANNABINOIDS; SEIZURE; DAMAGE; MODEL; FAAH;

D O I：

10.1021/acschemneuro.1c00192

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1716 / 1736

页数：21

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[61] Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder [J].