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Oxygenated Metabolites of Anandamide and 2-Arachidonoylglycerol: Conformational Analysis and Intera

Oxygenated Metabolites of Anandamide and 2-Arachidonoylglycerol: Conformational Analysis and Intera

  1. helikophis
    This study was aimed at finding structural requirements for the interaction of the acyl chain
    of endocannabinoids with cannabinoid receptors, membrane transporter protein, and fatty acid
    amide hydrolase (FAAH). To this end, the flexibility of the acyl chain was restricted by
    introduction of an 1-hydroxy-2Z,4E-pentadiene system in anandamide (N-arachidonoyletha-
    nolamine, AEA) and 2-arachidonoylglycerol (2-AG) at various positions using different
    lipoxygenases. This brought about selectivity and attenuated the binding potency of AEA and
    2-AG. Although the displacement constants were modest, 15(S)-hydroxy-eicosa-5Z,8Z,11Z,-
    13E-tetraenoyl-N-(2-hydroxyethyl)amine was found to bind selectively to the CB1 receptor,
    whereas its 1-arachidonoyl-sn-glycerol analogue and 13(S)-hydroxy-octadeca-9Z,11E-dienoyl-
    N-(2-hydroxyethyl)amine could selectively bind to the CB2 receptor. 11(S)-Hydroxy-eicosa-
    5Z,8Z,12E,14Z-tetraenoyl-N-(2-hydroxyethyl)amine did not bind to either receptor, whereas
    12(S)-hydroxy-eicosa-5Z,8Z,10E,14Z-tetraenoyl-N-(2-hydroxyethyl)amine did bind to both CB
    receptors with an affinity similar to that of AEA. All oxygenated anandamide derivatives were
    good inhibitors of FAAH (low micromolar Ki) but were ineffective on the AEA transporter.
    2-AG rapidly isomerizes into 1(3)-arachidonoyl-sn-glycerol. Both 1- and 3-arachidonoyl-sn-
    glycerol did not bind to either CB receptor and did not interfere with AEA transport. Thus,
    after it is isomerized, 2-AG is inactivated, thereby decreasing effective concentrations of 2-AG.
    Analysis of 1H NMR spectra revealed that chloroform did not induce notably different
    conformations in the acyl chain of 15(S)-hydroxy-eicosa-5Z,8Z,11Z,13E-tetraenoic acid as
    compared with water. Molecular dynamics (MD) simulations of AEA and its analogues in the
    presence of explicit water molecules revealed that a tightly folded conformation of the acyl
    chain is not the only requirement for CB1 binding. Structural details of the C2-C15 loop, such
    as an sp2 carbon at position 11, are necessary for receptor binding. The MD simulations may
    suggest that the average orientations of the pentyl tail of AEA and 12(S)-hydroxy-eicosa-5Z,8Z,-
    10E,14Z-tetraenoyl-N-(2-hydroxyethyl)amine are different from that of the low-affinity, inactive
    ligands.