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Journal of Biomolecular Screening
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High-Throughput Screening for the Discovery of Inhibitors of Fatty Acid Amide Hydrolase Using a Microsome-Based Fluorescent Assay

Yuren Wang

Wyeth Research Princeton, NJ 08543-8000 wangy4{at}wyeth.com

Fernando Ramirez

Chemical and Screening Sciences, Wyeth Research, Princeton, NJ

Girija Krishnamurthy

Adam Gilbert

Chemical and Screening Sciences, Wyeth Research, Pearl River, NY

Nina Kadakia

Chemical and Screening Sciences, Wyeth Research, Princeton, NJ

Jun Xu

Neuroscience Discovery Research, Wyeth Research, Princeton, NJ

Gary Kalgaonkar

Chemical and Screening Sciences, Wyeth Research, Princeton, NJ

Manjunath K. Ramarao

Inflammation Department, Wyeth Research, Cambridge, MA

Wade Edris

Kathryn E. Rogers

Philip G. Jones

Neuroscience Discovery Research, Wyeth Research, Princeton, NJ

Fatty acid amide hydrolase (FAAH) is a membrane-associated enzyme that catalyzes the hydrolysis of several endogenous bioactive lipids, including anandamide (AEA), N-palmitoylethanolamine (PEA), oleamide, and N-oleoylethanolamine (OEA). These fatty acid amides participate in many physiological activities such as analgesia, anxiety, sleep modulation, anti inflammatory responses, and appetite suppression. Because FAAH plays an essential role in controlling the tone and activity of these endogenous bioactive lipids, this enzyme has been implicated to be a drug target for the therapeutic management of pain, anxiety, and other disorders. In an effort to discover FAAH inhibitors, the authors have previously reported the development of a novel fluorescent assay using purified FAAH microsomes as an enzyme source and a fluorogenic substrate, arachidonyl 7-amino, 4-methyl coumarin amide (AAMCA). Herein, the authors have adapted this assay to a high-throughput format and have screened a large library of small organic compounds, identifying a number of novel FAAH inhibitors. These data further verify that this fluorescent assay is sufficiently robust, efficient, and low-cost for the identification of FAAH inhibitory molecules and open this class of enzymes for therapeutic exploration.

Key Words: high-throughput screening • fluorescent assay • fluorogenic substrate • fatty acid amide hydrolase • microsome

This version was published on August 1, 2006

Journal of Biomolecular Screening, Vol. 11, No. 5, 519-527 (2006)
DOI: 10.1177/1087057106288188
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