Cannabinoid Receptor Ligands
it has been cloned 28 and FAAH knockout mice
mechanism(s) underlying the entourage effect have
have been developed. 29,30 NAPE/PLD, 31 MAGL, 32-34
yet to be established.
and DAGL α and DAGL β 35 have also been cloned,
and mice with a genetic deletion of NAPE/PLD
neuromodulatory and immunomodulatory roles that
include inhibition of ongoing transmitter release
At least some effects induced by endogenously
through retrograde signalling 38 and regulation of
released anandamide and 2-arachidonylglycerol
cytokine release and of immune cell migration. 39,40
appear to be enhanced through what has been
It is also now generally accepted that there are
termed the “entourage effect”. This relies on
certain disorders in which endocannabinoid release
the co-release of other endogenous fatty acid
increases in particular tissues, and secondly, that this
upregulation of the endocannabinoid system leads
and oleamide, which can potentiate anandamide,
in some instances to the suppression of unwanted
signs and symptoms and so is “autoprotective” and in
which can potentiate 2-arachidonylglycerol. 37 The
others to the production of undesirable effects. 5 Thus
Table 1 | Pharmacological properties of certain cannabinoid CB 1 /CB 2 receptor agonists and their K i
values for the in vitro displacement of [ 3 H]CP 55,940 or [ 3 H]HU 243 from CB 1 - and CB 2 -specific binding
CB 1 K i
CB 2 K i
The compounds in this group consist of dibenzopyran derivatives and are either plant-derived
cannabinoids or synthetic analogues of these. Notable examples are
(–)- ∆ 9 -THC, which binds equally well to CB 1 and CB 2 receptors and behaves as a partial agonist
at both of these receptor types. It has even less efficacy at CB 2 than at CB 1 receptors and,
indeed, has been reported in one CB 2 bioassay system to behave as an antagonist. 42
(–)- ∆ 8 -THC, which resembles ∆ 9 -THC both in its affinities for CB 1 and CB 2 receptors and in its
CB 1 receptor efficacy.
(–)-11-hydroxy- ∆ 8 -THC-dimethylheptyl (HU 210), which has efficacies at CB 1 and CB 2 receptors
that match those of CP 55,940 and WIN 55,212-2 (see below) and affinities for CB 1 and CB 2
receptors that exceed those of many other cannabinoids. It is a particularly potent cannabinoid
receptor agonist and its pharmacological effects in vivo are exceptionally long-lasting. The
enhanced affinity and efficacy shown by HU 210 at cannabinoid receptors can be largely
attributed to the replacement of the pentyl side chain of ∆ 8 -THC with a dimethylheptyl group.
The compounds in this group were developed by a Pfizer research team. They are quite similar in
structure to classical cannabinoids, consisting as they do of bicyclic and tricyclic analogues of
∆ 9 -THC that lack a pyran ring.
The most widely used non-classical cannabinoid is CP 55,940, which has CB 1 and CB 2 affinities
in the low nanomolar range and exhibits relatively high efficacy at both of these receptor types.
Aminoalkylindole The prototype of this group is WIN 55,212-2, which was discovered by a Sterling Winthrop research
team and is widely used in cannabinoid research.
The structure of WIN 55,212-2 bears no resemblance to that of classical, nonclassical or
eicosanoid cannabinoids. Indeed, there is evidence that it binds differently to the CB 1 receptor
than classical and nonclassical cannabinoids, albeit it in a manner that still permits mutual
displacement between WIN 55,212-2 and non-aminoalkylindole cannabinoids at CB 1 binding
sites. Like CP 55,940, WIN 55,212-2 exhibits relatively high efficacy at CB 1 and CB 2 receptors
and possesses CB 1 and CB 2 affinities in the low nanomolar range. However, in contrast to CP
55,940, it has slightly greater affinity for CB 2 than for CB 1 receptors.
The prototypic and most investigated members of this group are the endocannabinoids,
anandamide and 2-arachidonylglycerol.
Anandamide binds marginally more readily to CB 1 than to CB 2 receptors and, when protected
from enzymic hydrolysis, exhibits a CB 1 affinity similar to that of (–)- ∆ 9 -THC. It also resembles
(–)- ∆ 9 -THC in behaving as a partial agonist at CB 1 and CB 2 receptors and in exhibiting lower CB 2
than CB 1 efficacy.
2-Arachidonylglycerol has been found in several investigations to have affinities for CB 1 and CB 2
receptors similar to those of anandamide but to exhibit higher CB 1 and CB 2 efficacy than
anandamide. In one recent investigation, however, performed with human CB 1 receptor-
containing tissue, this endocannabinoid was found to lack both detectable CB 1 receptor efficacy
at concentrations of up to 10 µ M and any significant CB 1 receptor affinity (K i > 10 µ M). 43
ND, not determined; THC, tetrahydrocannabinol. See Figure 1 for the structures of the compounds listed in this table. For further information see references 1, 2 and 41.