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

Cite this

Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol. / Ghafouri, N ; Tiger, G ; Razdan, R K ; Mahadevan, A ; Pertwee, R G ; Martin, B R ; Fowler, C J .

In: British Journal of Pharmacology, Vol. 143, 2004, p. 774-784.

Research output: Contribution to journalArticle

Ghafouri, N ; Tiger, G ; Razdan, R K ; Mahadevan, A ; Pertwee, R G ; Martin, B R ; Fowler, C J . / Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol. In: British Journal of Pharmacology. 2004 ; Vol. 143. pp. 774-784.
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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.",
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TY - JOUR

T1 - Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol

AU - Ghafouri, N

AU - Tiger, G

AU - Razdan, R K

AU - Mahadevan, A

AU - Pertwee, R G

AU - Martin, B R

AU - Fowler, C J

PY - 2004

Y1 - 2004

N2 - 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.

AB - 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.

KW - 2-arachidonoyl glycerol

KW - anandamide

KW - monoacylglycerol lipase

KW - fatty acid amide hydrolase

KW - endocannabinoid

KW - CANNABINOID RECEPTOR AGONIST

KW - MOUSE MONOGLYCERIDE LIPASE

KW - RAT-LIVER

KW - PHENYLMETHYLSULFONYL FLUORIDE

KW - MOLECULAR CHARACTERIZATION

KW - ANANDAMIDE AMIDOHYDROLASE

KW - ENDOCANNABINOID SYSTEM

KW - NOLADIN ETHER

KW - CB1 RECEPTOR

KW - BRAIN

U2 - 10.1038/sj.bjp.0705948

DO - 10.1038/sj.bjp.0705948

M3 - Article

VL - 143

SP - 774

EP - 784

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

ER -