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
  • SR141716A but not AM 251 can antagonise
  • 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
    PIA
    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
    (Bold Link Text Denotes Compounds Available From Tocris)
    Page 9