Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.

The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid), and anandamide (an endogenous ligand for cannabinoid receptors) is detailed. The inhibitors may serve as useful tools to clarify the role of endogenous oleamide and anandamide and may prove to be useful therapeutic agents for the treatment of sleep disorders or pain. The combination of several features-an optimal C12-C8 chain length, -unsaturation introduction at the corresponding arachidonoyl ⌬ 8,9 ͞⌬ 11,12 and oleoyl ⌬ 9,10 location, and an ␣-keto N4 oxazolopyridine with incorporation of a second weakly basic nitrogen provided FAAH inhibitors with Kis that drop below 200 pM and are 10 2 -10 3 times more potent than the corresponding trifluoromethyl ketones.

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The three-phase equilibrium (pressure-temperature) relation of the difluoromethane + water binary system containing gas hydrates was measured in the pressure range from (0.20 to about 11.0) MPa and temperature range from (275.15 to 300.15) K. On the basis of each three-phase equilibrium curve, the quadruple point which consists of gaseous and liquid difluoromethane, water, and hydrate was determined as 1.45 MPa and 293.16 K. The in situ Raman spectroscopy under the three-phase (gas, water, and hydrate) equilibrium conditions showed that the crystal structure of difluoromethane gas hydrate was structure-I, where both small and large cages were occupied by the difluoromethane molecule. The overall hydration enthalpy of simple structure-I difluoromethane gas hydrate under the three-phase equilibrium conditions was evaluated by means of the Clapeyron equation.