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 ondemand protective response to seizures. Blocking endocannabinoids' 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.

Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition

“…In the last few years, academic and industrial efforts have been strongly focused on the development of selective FAAH or MAGL inhibitors with potential therapeutic application in several diseases such as MS, epilepsy, neuropathic pain, and chronic pain disorders [86,144,[154][155][156]. However, the simultaneous inhibition of the two main ECS catabolic enzymes also appears as a promising therapeutic strategy.…”

Inhibition ofFAAHsuppressesRANKL‐induced osteoclastogenesis and attenuates ovariectomy‐induced bone loss partially through repressing theIL17pathway

“…63 Previous research has shown that FAAH inhibitors can reduce the oxidative state by reducing the DNAbinding activity of NF-κB p65 without cytotoxicity. 64 Our results showed that both genetic and pharmacological inhibition of FAAH could inhibit RANKL-induced NF-κB and MAPK signaling pathways, suggesting that FAAH inhibition can suppress RANKL-induced osteoclast differentiation by inhibiting NF-κB and MAPK pathways activation. It is worth noting that the process of signal transduction is transient, the expression of signaling molecules increased rapidly after stimulation, reached a peak at about 15 min, and then quickly decreased.…”

Synthesis of Unsymmetrical Squaramides as Allosteric GSK‐3β Inhibitors Promoting β‐Catenin‐Mediated Transcription of TCF/LEF in Retinal Pigment Epithelial Cells

“…Solubility and chemical stability have been determined at 25 °C using HPLC protocol, as previously reported by us [42,48] . Briefly, a Chromolith HPLC column RP‐18 was employed.…”

“…Solubility and chemical stability have been determined at 25 °C using HPLC protocol, as previously reported by us. [42,48] Briefly, a Chromolith HPLC column RP-18 was employed. The analysis were performed at 25 °C using a gradient elution mixture of MeCN/H 2 O (with 0.1 % TFA as the phase modifier) starting from a 0 % to 20 % MeCN in 4 min and then up to 50 % MeCN in 3 min with flow speed of 0.8 mL/min.…”