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Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.

ABSTRACT: Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.

SUBMITTER: Ahn K

PROVIDER: S-EPMC2692831 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.

Ahn Kay K Johnson Douglas S DS Mileni Mauro M Beidler David D Long Jonathan Z JZ McKinney Michele K MK Weerapana Eranthie E Sadagopan Nalini N Liimatta Marya M Smith Sarah E SE Lazerwith Scott S Stiff Cory C Kamtekar Satwik S Bhattacharya Keshab K Zhang Yanhua Y Swaney Stephen S Van Becelaere Keri K Stevens Raymond C RC Cravatt Benjamin F BF

Chemistry & biology 20090401 4

Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inh ...[more]

PMID: 19389627

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Project description:BACKGROUND: Anandamide and 2-arachidonoylglycerol are neuromodulatory lipids interacting with cannabinoid receptors, whose availability is regulated by the balance between 'on demand' generation and enzymatic degradation [by fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase]. Given the reported effects of anandamide on dopamine transmission, we investigated the influence of endocannabinoids and URB597, a well-known FAAH inhibitor, on the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. EXPERIMENTAL APPROACH: We investigated TH expression in N1E115 neuroblastoma using a reporter gene assay, as well as mRNA and protein quantifications. FAAH inhibition was confirmed by measuring radiolabelled substrate hydrolysis and endogenous endocannabinoids. KEY RESULTS: Anandamide decreased TH promoter activity in N1E115 cells through CB? receptor activation. Unexpectedly, URB597 reduced TH expression (pEC?? = 8.7 ± 0.2) through FAAH-independent mechanisms. Indeed, four structurally unrelated inhibitors of FAAH had no influence on TH expression, although all the inhibitors increased endocannabinoid levels. At variance with the endocannabinoid responses, the use of selective antagonists indicated that the URB597-mediated decrease in TH expression was not directed by the CB? receptor, but rather by abnormal-cannabidiol-sensitive receptors and PPARs. Further supporting the physiological relevance of these in vitro data, URB597 administration resulted in reduced TH mRNA levels in mice brain. CONCLUSIONS: While confirming the implication of endocannabinoids on the modulation of TH, we provide strong evidence for additional physiologically relevant off-target effects of URB597. In light of the numerous preclinical studies involving URB597, particularly in anxiety and depression, the existence of non-CB? and non-FAAH mediated influences of URB597 on key enzymes of the catecholaminergic transmission system should be taken into account when interpreting the data.

Dataset Information

Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.

Publications

Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.

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