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. Author manuscript; available in PMC: 2014 Mar 1.
Published in final edited form as: Nat Neurosci. 2013 Aug 4;16(9):1291–1298. doi: 10.1038/nn.3480

Figure 1. Molecular determinants of substrate-selective pharmacology.

Figure 1

(a) The crystal structure of indomethacin bound to mCOX-2 highlighting the interactions between the inhibitor and Arg-120 and Tyr-355 of the COX-2 active site. (b) Indomethacin inhibition of AA (blue), 2-AG (red), and AEA (grey) oxygenation by WT mCOX-2. (c) Indomethacin inhibition of 2-AG (red) but not AA (blue) oxygenation by R120Q COX-2. (d) Indomethacin inhibition of 2-AG (red) but not AA (blue) oxygenation by Y355F COX-2. (e) Conversion of indomethacin to LM-4131, an SSIC. (f) LM-4131 inhibition of AEA (grey) and 2-AG (red), but not AA (blue), oxygenation by WT mCOX-2. (g) Inhibition of 2-AG (red), but not AA (blue), oxygenation by COX-2 in stimulated RAW 264.7 macrophages by LM-4131. (h) Levels of 2-AG (red) and AA (blue) in stimulated RAW 264.7 macrophages in response to increasing concentrations of LM-4131. LM-4131 significantly increased 2-AG levels at 0.75 μM, 1.5 μ M, and 3 μM. Data shown are mean ± S.E.M with n = 3 cell plates for each point. Significance determined using a two-way ANOVA followed by Holm-Sidak's multiple comparisons post-test. (i) Effects of LM4131, PF-3845, and URB597 on FAAH activity. (j) Effects of LM-4131 and JZL-184 on MAGL activity. (k) Effects of LM-4131 and THL on DAGL activity.