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),
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
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
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
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
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
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
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
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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