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. Author manuscript; available in PMC: 2014 Jul 19.
Published in final edited form as: ACS Chem Biol. 2013 May 23;8(7):1590–1599. doi: 10.1021/cb400261h

Figure 2.

Figure 2

Design and in vitro and in vivo characterization of JW651. (a) Structures of previously developed MAGL inhibitors JZL184 and KML29 leading to the simplified benzhydrylpiperazine scaffold of JW651. (b) In vitro competitive ABPP of JW651 using the serine hydrolase-directed probe FP-Rh in the membrane fraction of the mouse brain proteome. JW651 potently and selectively inhibits FP-Rh labeling of MAGL, with ABHD6 being the only detectable off-target (up to 100 μM JW651). (c) In vivo competitive ABPP of brain proteomes isolated from JW651-treated mice (1.0 – 40 mg•kg–1, p.o.) 4 h after administration. JW651 completely inhibits MAGL in the brain at doses as low as 5 mg•kg–1 (See also Supplementary Figure S1 for endocannabinoid levels in the brain for JW651 treated mice).