Figure 11 | Structures of the CB 1 allosteric ligands, Org 27569, Org 29647 and Org 27759, the
CB 2 -selective antagonist/inverse agonist, Sch.336, and the endogenous fatty acid amide,
palmitoylethanolamide
Cl
O
F
O
Cl
O
N
HN
N
HN
H
N
H
N
N
HN
N
H
Org 27569
Org 29647
Org 27759
O
O
MeO
S
N
H
S
O
S
O
O
O
O
OH
N
MeO
H
Sch.336
(Bold Link Text Denotes Compounds Available From Tocris)
Org 27569, Org 29647 and Org 27759 have been
Future Directions
found to behave as CB 1 allosteric enhancers in
This review has focused particularly on ligands that
binding assays but as CB 1 allosteric inhibitors in
are most widely used as experimental tools either to
functional in vitro bioassays, 127 limiting their use as
target cannabinoid CB 1 and/or CB 2 receptors directly
experimental tools and creating a need for additional
or to modulate tissue levels of endocannabinoids
CB 1 allosteric modulators.
following their endogenous release. It is likely
that future research in the area of cannabinoid
Three other noteworthy ligands are Sch.336
pharmacology will be directed at:
(Figure 11), HU 211 which is the (+)-enantiomer of the
potent CB 1 /CB 2 receptor agonist HU 210 (Figure 1),
  • exploring
  • the
    structure-activity
    relationships
    and the endogenous ligand, palmitoylethanolamide
    of ligands that target the CB 1 allosteric site or
    (Figure 11). Sch.336 is a CB 2 -selective antagonist/
    that behave as neutral CB 1 and/or CB 2 receptor
    inverse agonist that exhibits even greater efficacy
    antagonists;
    and potency as a CB 2 receptor inverse agonist than
  • assessing the therapeutic potential of CB 1 and/or
  • SR144528. 128 This high inverse efficacy of Sch.336
    CB 2 receptor allosteric modulators and neutral
    may account for its ability to inhibit leukocyte
    antagonists;
    migration/trafficking, an effect that could come to
  • gathering more conclusive evidence for or against
  • be exploited in the clinic for the management of
    the presence of an endocannabinoid transporter
    inflammatory disorders. 128 HU 211 lacks significant
    in mammalian cells;
    affinity for CB 1 or CB 2 receptors but possesses
  • establishing the pharmacological profiles of new
  • neuroprotective properties that may arise from its
    and existing modulators of endocannabinoid
    ability to behave as a non-competitive antagonist
    biosynthesis, metabolism or cellular uptake;
    at the N -methyl- D -aspartate (NMDA) receptor, to
  • finding out why CB 2 receptors seem to be
  • decrease tumour necrosis factor- α production, to
    expressed by central neurons;
    inhibit depolarisation-evoked calcium fluxes and/
    or to scavenge oxygen-derived free radicals. 2,129
  • validating and characterising non-CB 1 , non-CB 2
  • Palmitoylethanolamide is of interest because it lacks
    targetsforparticularcannabinoids,anddeveloping
    significant affinity for CB 1 or CB 2 receptors and yet is
    compounds that can selectively activate or block
    susceptible to antagonism by SR144528, a finding
    such targets with reasonable potency;
    which has prompted the hypothesis that this fatty
  • following up early indications that cannabinoid
  • acid amide may be the endogenous agonist for a
    receptors may exist as homodimers or form
    “CB 2 -like” receptor. 2,88 There is also evidence, first
    heterodimers or oligomers with one or more
    that palmitoylethanolamide is a PPAR- α receptor
    classes of non-cannabinoid receptor; 2
    agonist, 130 second that it is metabolised both by
  • obtaining a more complete understanding of the
  • FAAH and PAA, 5 and third that it may potentiate
    part played by the endocannabinoid system in
    anandamide through the so-called “entourage effect”
    ameliorating the symptoms and/or the underlying
    (see section on the endocannabinoid system).
    pathology of certain disorders.
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