Because cannabinoid receptor agonists differ in the
Figure 6 | Structures of the DAGL inhibitors,
extent to which they interact with the proposed or
tetrahydrolipstatin and O-3841
establishednon-CB 1 ,non-CB 2 targetslistedinTable3,
it follows that some ligands that appear to activate CB 1
and/or CB 2 receptors with similar potencies will most
NHCHO
probably possess different pharmacological profiles
from each other. It is also worth noting that although
O
O
O
O
there are a number of established cannabinoid
receptor ligands that exhibit marked selectivity as
agonists or antagonists/inverse agonists for CB 1 or
CB 2 receptors (see previous sections), none of these
Tetrahydrolipstatin
ligands are entirely CB 1 - or CB 2 -specific. Thus, each
of these ligands is expected to activate or block both
O
F
of these receptor types equally well if administered at
O
P
O
Me
a sufficiently high dose or concentration and hence
O
to exhibit selectivity only when administered at lower
OMe
doses or concentrations that lie within its CB 1 or CB 2
“selectivity window”.
O-3841
Inhibitors of 2-Arachidonylglycerol
Biosynthesis
and of putative non-I 1 , non-I 2 imidazoline receptors
Since
and
and
are synthesised on demand rather than stored,
and since there is evidence that increased
production and release of either or both of these
WIN 55,212-2-induced
activation
of
central
endocannabinoids is responsible for unwanted signs
presynaptic putative TRPV1-like receptors.
and symptoms of certain disorders (see section on
Future research will most likely reveal additional
the endocannabinoid system), selective inhibitors of
targets for CB 1 and CB 2 receptor ligands. Indeed,
their enzymic biosynthesis would not only constitute
it has already been claimed in AstraZeneca and
important experimental tools but also have potential
GlaxoSmithKline patents that some established
as therapeutic agents.Although selective inhibitors of
cannabinoid receptor agonists (and antagonists)
NAPE-PLD have yet to be discovered, such inhibitors
activate the G-protein-coupled orphan receptor,
are available for the enzymes, DAGL α and DAGL β ,
GPR55. 97,98
which catalyse the conversion of diacylglycerols
Figure 7 | Structures of the FAAH inhibitors, AM 374, O-1887, PIA, PMSF, MAFP, URB532, URB597,
OL-135, AACOCF 3 (ATFMK) and N -arachidonylglycine (see also Table 4), and of the MAGL inhibitor, URB602
O
O
O
S
OMe
F
P
N
H
O
F
AM 374
O-1887
O
NH 2
O
H
O
N
O
OMe
P
S
F
O
H
F
O
O
N
O
O
PMSF
URB532
URB597
O
O
N
N
H
N
O
O
CF 3
N
CO 2 H
H
O
O
OL-135
URB602
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