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Inhibition of fatty acid amide hydrolase by BIA 10-2474 in rat brain.

ABSTRACT: In a recent clinical trial, the drug BIA 10-2474, a putative fatty acid amide hydrolase(FAAH) inhibitor, was responsible for severe adverse events (SAEs), including one death. To date, there has been little reliable information divulged about the potency of BIA 10-2474 at FAAH in the central nervous system. We synthesised BIA 10-2474 and determined its ability to inhibit FAAH ex vivo in rat brain using a FAAH selective radiotracer. BIA 10-2474 proved to be a potent FAAH inhibitor with IC₅₀s of 50-70?µg/kg (i.p.) in various brain regions. This information may be useful for determining the cause of the SAEs.

SUBMITTER: Tong J

PROVIDER: S-EPMC5669339 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Inhibition of fatty acid amide hydrolase by BIA 10-2474 in rat brain.

Tong Junchao J Mizrahi Romina R Houle Sylvain S Kish Stephen J SJ Boileau Isabelle I Nobrega Jose J Rusjan Pablo M PM Wilson Alan A AA

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20161001 11

In a recent clinical trial, the drug BIA 10-2474, a putative fatty acid amide hydrolase(FAAH) inhibitor, was responsible for severe adverse events (SAEs), including one death. To date, there has been little reliable information divulged about the potency of BIA 10-2474 at FAAH in the central nervous system. We synthesised BIA 10-2474 and determined its ability to inhibit FAAH ex vivo in rat brain using a FAAH selective radiotracer. BIA 10-2474 proved to be a potent FAAH inhibitor with IC<sub>50< ...[more]

PMID: 27650910

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Project description:Although cannabinoids are efficacious in laboratory animal models of inflammatory pain, their established cannabimimetic actions diminish enthusiasm for their therapeutic development. Conversely, fatty acid amide hydrolase (FAAH), the chief catabolic enzyme regulating the endogenous cannabinoid N-arachidonoylethanolamine (anandamide), has emerged as an attractive target for treating pain and other conditions. Here, we tested WIN 55212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de)-1,4-benzoxazin-6-yl]-1-napthalenylmethanone], a cannabinoid receptor agonist, and genetic deletion or pharmacological inhibition of FAAH in the lipopolysaccharide (LPS) mouse model of inflammatory pain. WIN 55212-2 significantly reduced edema and hot-plate hyperalgesia caused by LPS infusion into the hind paws, although the mice also displayed analgesia and other central nervous system effects. FAAH(-/-) mice exhibited reduced paw edema and hyperalgesia in this model without apparent cannabimimetic effects. Transgenic mice expressing FAAH exclusively on neurons continued to display the antiedematous, but not the antihyperalgesic, phenotype. The CB(2) cannabinoid receptor (CB(2)) antagonist SR144528 [N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide] blocked this non-neuronal, anti-inflammatory phenotype, and the CB(1) cannabinoid receptor (CB(1)) antagonist rimonabant [SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] blocked the antihyperalgesic phenotype. The FAAH inhibitor URB597 [cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester] attenuated the development of LPS-induced paw edema and reversed LPS-induced hyperalgesia through the respective CB(2) and CB(1) mechanisms of action. However, the transient receptor potential vanilloid type 1 antagonist capsazepine did not affect either the antihyperalgesic or antiedematous effects of URB597. Finally, URB597 attenuated levels of the proinflammatory cytokines interleukin-1beta and tumor necrosis factor alpha in LPS-treated paws. These findings demonstrate that simultaneous elevations in non-neuronal and neuronal endocannabinoid signaling are possible through inhibition of a single enzymatic target, thereby offering a potentially powerful strategy for treating chronic inflammatory pain syndromes that operate at multiple levels of anatomical integration.

Project description:BackgroundThe brain's endocannabinoid system, the primary target of cannabis, has been implicated in psychosis. The endocannabinoid anandamide is elevated in cerebrospinal fluid of patients with schizophrenia. Fatty acid amide hydrolase (FAAH) controls brain anandamide levels; however, it is unknown if FAAH is altered in vivo in psychosis or related to positive psychotic symptoms.MethodsTwenty-seven patients with schizophrenia spectrum disorders and 36 healthy control subjects completed high-resolution positron emission tomography scans with the novel FAAH radioligand [11C]CURB and structural magnetic resonance imaging. Data were analyzed using the validated irreversible 2-tissue compartment model with a metabolite-corrected arterial input function.ResultsFAAH did not differ significantly between patients with psychotic disorders and healthy control subjects (F1,62.85 = 0.48, p = .49). In contrast, lower FAAH predicted greater positive psychotic symptom severity, with the strongest effect observed for the positive symptom dimension, which includes suspiciousness, delusions, unusual thought content, and hallucinations (F1,26.69 = 12.42, p = .002; Cohen's f = 0.42, large effect). Shorter duration of illness (F1,26.95 = 13.78, p = .001; Cohen's f = 0.39, medium to large effect) and duration of untreated psychosis predicted lower FAAH (F1,26.95 = 6.03, p = .021, Cohen's f = 0.27, medium effect). These results were not explained by past cannabis exposure or current intake of antipsychotic medications. FAAH exhibited marked differences across brain regions (F7,112.62 = 175.85, p < 1 × 10-56; Cohen's f > 1). Overall, FAAH was higher in female subjects than in male subjects (F1,62.84 = 10.05, p = .002; Cohen's f = 0.37).ConclusionsThis first study of brain FAAH in psychosis indicates that FAAH may represent a biomarker of disease state of potential utility for clinical studies targeting psychotic symptoms or as a novel target for interventions to treat psychotic symptoms.

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Inhibition of fatty acid amide hydrolase by BIA 10-2474 in rat brain.

Publications

Inhibition of fatty acid amide hydrolase by BIA 10-2474 in rat brain.

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