analogue, AM 374, for irreversible FAAH inhibition,
and OL-135 for reversible FAAH inhibition. Thus,
LY 2183240, Highly Potent Inhibitor
these compounds can all produce their inhibitory
effects in vitro at concentrations that lie in the low
of Anandamide Uptake
nanomolar range and that lack the ability to displace
radiolabelled ligands from CB 1 receptors or (where
Cat. No. 2452
N
N
N
this has been investigated) from CB 2 receptors
N
(Figure 7 and Table 4). It should be noted, however,
NMe 2
O
that the pharmacological characterisation of most of
these inhibitors is incomplete.
LY 2183240 is a novel and exceptionally potent blocker
of anandamide uptake (IC 50 = 270 pM). It appears to act
The compound O-1887 is a structural analogue
via inhibition of fatty acid amide hydrolase (FAAH) activity
of methyl arachidonyl fluorophosphonate (MAFP;
(IC 50 = 12.4 nM). Following i.p. administration in rats,
Figure 7), which is itself an irreversible FAAH inhibitor
LY 2183240 increases anandamide concentrations in the
cerebellum and exerts significant antinociceptive effects in
(IC 50 = 1 to 3 nM) that additionally inhibits both MAGL
the formalin model of persistent pain.
(IC 50 = 2 to 800 nM) and DAGL (IC 50 = 800 nM)
Moore et al (2005) Identification of a high-affinity binding site involved in the
although not NAPE-PLD, and potently displaces
transport of endocannabinoids. Proc.Natl.Acad.Sci.USA 102 17852. Dickason-
[ 3 H]CP 55,940 from specific binding sites on rat
Chesterfield et al (2006) Pharmacological characterization of endocannabinoid
brain membranes in an irreversible manner (IC 50 =
transport and fatty acid amide hydrolase inhibitors. Cell Mol.Neurobiol. (in
press). Alexander and Cravatt (2006) The putative endocannabinoid transport
20 nM). 5,99,100,104 There has also been one report
blocker LY2183240 is a potent inhibitor of FAAH and several other brain serine
that MAFP behaves as an irreversible CB 1 receptor
hydrolases. J.Am.Chem.Soc. 128 9699.
antagonist 118 and a second report that it does not. 54
(Sold under licence from Eli Lilly and Company)
Turning now to compounds that block the metabolism
of 2-arachidonylglycerol by inhibiting MAGL, a
Inhibitors of the Cellular Uptake of
number of these have now been identified. 99,100,119,120
Anandamide
At present, the best and most characterised inhibitor
The first inhibitor of the cellular uptake of anandamide
of this enzyme seems to be URB602 (Figure 7),
to
be
developed
was
N -(4-hydroxyphenyl)
which produces non-competitive inhibition of MAGL
arachidonylamide (AM 404) (Figure 8). However,
at micromolar concentrations (IC 50 = 28 µ M) and
this compound is not particularly selective as it also
lacks any detectable ability to inhibit FAAH at 100 µ M
inhibits FAAH, binds to CB 1 receptors and activates
or to displace [ 3 H]WIN 55,212-2 from CB 1 or CB 2
TRPV1 receptors at concentrations at or below those
receptors at 5 µ M. 119 Another compound, URB754,
at which it has been reported to inhibit anandamide
has been reported to inhibit MAGL with significantly
uptake (Table 4). Other inhibitors of anandamide
greater potency than URB602. 120 However, it is now
uptake are now available (Figure 8), 5,23,100 and the
known that this inhibition was induced by an impurity
potencies exhibited by some of these not only as
present in a commercial sample of URB754, and that
uptake inhibitors but also (when known) as inhibitors
the pure compound lacks significant activity as an
of FAAH, as CB 1 and CB 2 receptor ligands and as
MAGL inhibitor at concentrations of up to 100 µ M
TRPV1 receptor agonists are shown in Table 4.
(personal communication from Dr Daniele Piomelli).
Importantly, it is currently unclear whether any of the
Figure 8 | Structures of AM 404, VDM 11, UCM 707, OMDM-1, OMDM-2, LY 2183240 and
5´-dimethylheptyl-cannabidiol ((–)-5´-DMH-CBD), all of which behave as inhibitors of anandamide
cellular uptake
OH
OH
O
O
O
N
N
N
H
H
H
O
OH
OH
OH
O
O
N
N
N
OH
OH
N
N
N
H
H
NMe 2
O
OH
OMDM-1 ( S )
(Bold Link Text Denotes Compounds Available From Tocris)
Page 11