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Chembiomolecular Science pp 37–49Cite as

Inhibitors of Fatty Acid Amide Hydrolase

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Abstract

High pressure liquid chromatography (HPLC) fractionation of the cerebrospinal fluid (CSF) from sleep-deprived cats led to the detection of a substance that accumulated under conditions of sleep deprivation [1]. FABHRMS provided a best-fit molecular formula of C18H35NO and MS2/MS3revealed a lipid fragmentation pattern. Given the simplicity of the molecule, candidate lipid structures incorporating the molecular formula and correct degree of unsaturation were prepared and correlated with the endogenous substance (Fig. 1) [2]. Oleamide (1) proved identical with the authentic material and, with a recognition of its characteristics and solubility properties, sufficient amounts (300–400 μg) of the endogenous lipid were isolated from the CSF to permit an unambiguous correlation [2, 3]. Oleamide was shown to induce physiological sleep in rats, mice, and cats in a dose-dependent manner [3]. As in physiological sleep, the sleeping animals maintained the ability to respond to sound with an orienting reflex and attention directed toward the source. The examination of a number of close structural analogues revealed that this effect is specific for oleamide. These studies identified oleamide as an endogenous signaling fatty acid amide and provided the second prototypical member of a new and growing class of signaling molecules: fatty acid amides [4, 5].

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Acknowledgments

We gratefully acknowledge the financial support of the National Institutes of Health (DA015648), and the efforts of our long-time collaborators (R.A. Lerner, B.F. Cravatt, S.J. Henriksen, N.B. Gilula, G. Siuzdak, A.H. Lichtman, E.J. Bilsky, and R.C. Stevens).

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Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA

    Dale L. Boger

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  1. Dale L. Boger
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Correspondence to Dale L. Boger .

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Editors and Affiliations

  1. Institute of Microbial Chemistry, Kamioosaki 3-14-23, Tokyo, 141-0021, Japan

    Masakatsu Shibasaki

  2. The University of Tokyo, Department of Pharmacology, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, 113-0033, Japan

    Masamitsu Iino

  3. RIKEN Advanced Science Institute, Antibiotics Laboratory, Chemical Biology Core Facility, 2-1, Hirosawa, Wako, 351-0198, Saitama, Japan

    Hiroyuki Osada

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Boger, D.L. (2012). Inhibitors of Fatty Acid Amide Hydrolase. In: Shibasaki, M., Iino, M., Osada, H. (eds) Chembiomolecular Science. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54038-0_4

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