Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol

N Ghafouri, G Tiger, R K Razdan, A Mahadevan, R G Pertwee, B R Martin, C J Fowler

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Abstract

1 The pharmacology of monoacylglycerol lipase (MAGL) is not well understood. In consequence, the abilities of a series of analogues of 2-arachidonoylglycerol (2-AG) to inhibit cytosolic 2-oleoylglycerol and membrane-bound anandamide hydolysis by MAGL and fatty acid amide hydrolase (FAAH), respectively, have been investigated.

2 2-AG and its 1-regioisomer (1-AG) interacted with MAGL with similar affinities (IC50 values 13 and 17 muM, respectively). Shorter homologues of 2-AG (2-linoleoylglycerol and 2-oleoylglycerol) had affinities for MAGL similar to 2-AG. This pattern was also seen when the arachidonoyl side chain of arachidonoyl trifluoromethylketone was replaced by an oleoyl side chain.

3 Arachidonoyl serinol (IC50 value 73 muM) was a weaker inhibitor of MAGL than 2-AG. The IC50 values of noladin ether towards MAGL and FAAH were 36 and 3 muM, respectively. Arachidonoyl glycine interacted with FAAH (IC50 value 4.9 muM) but only weakly interacted with MAGL (IC50 value 4100 muM).

4 alpha-Methyl-1-AG had similar potencies towards MAGL and FAAH (IC50 values of 11 and 33 muM, respectively). O-2203 (1-(20-cyano-16,16-dimethyl-eicosa-5,8,11,14-tetraenoyl) glycerol) and O-2204 (2-(20-hydroxy-16,16-dimethyl-eicosa-5,8,11,14-tetraenoyl) glycerol) were slightly less potent, but again affected both enzymes equally. alpha-Methyl-1-AG, O-2203 and O-2204 interacted only weakly with cannabinoid CB1 receptors expressed in CHO cells (K-i values 1.8, 3.7 and 3.2 muM, respectively, compared with 0.24 muM for 1-AG) and showed no evidence of central cannabinoid receptor activation in vivo at doses up to 30mg kg(-1) i.v.

5 It is concluded that compounds like a- Methyl-1-AG, O-2203 and O-2204 may be useful as leads for the discovery of selective MAGL inhibitors that lack direct effects upon cannabinoid receptors.

Original languageEnglish
Pages (from-to)774-784
Number of pages11
JournalBritish Journal of Pharmacology
Volume143
DOIs
Publication statusPublished - 2004

Keywords

  • 2-arachidonoyl glycerol
  • anandamide
  • monoacylglycerol lipase
  • fatty acid amide hydrolase
  • endocannabinoid
  • CANNABINOID RECEPTOR AGONIST
  • MOUSE MONOGLYCERIDE LIPASE
  • RAT-LIVER
  • PHENYLMETHYLSULFONYL FLUORIDE
  • MOLECULAR CHARACTERIZATION
  • ANANDAMIDE AMIDOHYDROLASE
  • ENDOCANNABINOID SYSTEM
  • NOLADIN ETHER
  • CB1 RECEPTOR
  • BRAIN

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