Cannabinoid Receptor Ligands
to 2-arachidonylglycerol. One of these inhibitors is
directedatexploringboththepharmacologicalactions
tetrahydrolipstatin (Figure 6), which inhibits DAGL α
of endocannabinoids when these are administered
(IC 50 = 60 nM) and DAGL β (IC 50 = 100 nM) far more
exogenously and their physiological and pathological
potently than it inhibits NAPE-PLD (IC 50 = 10 µ M)
roles when they are released endogenously. Indeed,
and which does not inhibit MAGL even at 25 µ M. 35,99
partly as a result of experiments with FAAH and
A second notable DAGL inhibitor is O-3841 (Figure 6).
MAGL inhibitors, there is already evidence that
This inhibits DAGL α at nanomolar concentrations
endogenous cannabinoid release increases in some
(IC 50 = 160 nM) but, at concentrations of up to 25 µ M,
disorders in a manner that leads to an amelioration
lacks any detectable inhibitory effect on NAPE-PLD,
of unwanted signs and symptoms (see section on
FAAH, MAGL or triacylglycerol lipase activity or on
the endocannabinoid system), and consequently,
the specific binding of [ 3 H]CP 55,940 to human CB 1
that such inhibitors have therapeutic potential.
or CB 2 receptors. 99 Whereas tetrahydrolipstatin and
O-3841 both inhibit DAGL in membrane preparations,
Following
the
discovery
of
anandamide,
the
only tetrahydrolipstatin has so far been found to
compound most widely used to inhibit its enzymic
produce detectable signs of DAGL inhibition in intact
hydrolysis (irreversibly) was the non-selective
cells. 99
serine protease inhibitor, phenylmethylsulphonyl
fluoride (IC 50 for FAAH inhibition = 290 nM to 15 µ M),
Inhibitors of the Enzymic Hydrolysis
which also inhibits MAGL, albeit less potently
of Endocannabinoids
(IC 50 ≥ 155 µ M). 100 Additional inhibitors of FAAH
The presence of FAAH and MAGL in many tissues
have now been developed, 5,23,100 the best of these for
has created the need for selective inhibitors of these
use as research tools most probably being URB597,
enzymes that can be used to facilitate research
O-1887, URB532 and the palmitylsulphonyl fluoride
Table 4 | Some inhibitors of fatty acid amide hydrolase (FAAH) or anandamide cellular uptake
Uptake
FAAH inhibition
CB 1
CB 2
TRPV1
Inhibitor
inhibition
IC 50 or K i *
IC 50 or K i *
IC 50 or K i *
EC 50 or K i *
Reference
IC 50 or K i * ( µ M)
( µ M)
( µ M)†
( µ M)†
( µ M)§
(a) FAAH
PMSF◊
ND
0.29 to 15
> 10
ND
ND
100, 101
inhibitors
AM 374◊
ND
0.013, 0.05
0.52
ND
ND
101, 102
MAFP #
ND
0.001 to 0.003
0.02
ND
ND
103, 104
O-1887◊
ND
0.015
> 10
ND
ND
105
URB532◊
> 300
0.214, 0.396
> 300
> 300
ND
106
URB597◊
> 30
0.0005, 0.0046
> 100
> 100
ND
106
OL-135
ND
0.0021
> 10
> 10
ND
107
PIA
§§
12.9
> 100
> 100
ND
108
ND
0.7 to 4
0.65
ND
ND
100, 109
> 50
4.1, 7
> 10
ND
> 10
110, 111
(b) Uptake
0.00027
0.0124
ND
ND
ND
27, 131
inhibitors
OMDM-1
2.4*, 2.6, > 20
> 50*, > 100
12.1*
> 10
> 10
112, 113
3*, 3.2, 17
> 50*, 54, > 100
5.1*
> 10
10
112, 113
6.1 to 11.2
1.2 to 3.7, > 50
> 5 or 10*
> 5 or 10*
Little activity at
113, 114
10 µ M
0.8, 25, 41
30, > 100
4.7*
0.067*
> 5*
113, 115
1 to 11
0.5 to 5.9
> 1*, 1.76*
13*
0.026
51, 63, 113,
22, > 30
114, 116
14
> 100
> 10*
1.8*
Inactive
117
(Bold Text Denotes Compounds Available From Tocris)
AACOCF 3 (ATFMK), arachidonyl trifluoromethyl ketone; (–)-5´-DMH-CBD, (–)-5´-dimethylheptyl-cannabidiol; MAFP, methyl arachidonyl fluorophosphonate; ND, no
data; PIA, palmitoylisopropylamide; PMSF, phenylmethylsulphonyl fluoride.
†IC 50 or K i values for displacement of [ 3 H]SR141716A (CB 1 receptors) or of [ 3 H]CP 55,940, [ 3 H]WIN 55,212-2 or [ 3 H]HU 243 (CB 1 and/or CB 2 receptors).
§EC 50 value for TRPV1 receptor activation.
◊Irreversible FAAH inhibitor.
#Irreversible CB 1 ligand.
§§Some inhibition of uptake at 30 and 100 µ M
LY 2183240 is also a potent inhibitor of other serine hydrolases and of MAGL. 27
OMDM-1 does not inhibit NAPE-PLD, DAGL α or MAGL at 25 µ M. 99
MAGL is not inhibited by URB532 or URB597 at 30 µ M 106 or by OL-135 at 100 µ M. 107
The structures of the inhibitors mentioned in this table are shown in Figures 7 and 8.
Page 10