compounds that are most widely used in cannabinoid
CP 55,940, Potent CB 1 and CB 2
research as experimental tools. Whenever possible,
Agonist
previous review articles have been cited that
OH
provide more detailed information and list additional
references.
Cat. No. 0949
OH
OH
Mixed CB 1 /CB 2 Receptor Agonists
As has been detailed elsewhere, 1,2,41 compounds
Me
Me
that are known to activate CB 1 and CB 2 receptors
CP 55,940 is a cannabinoid agonist that is considerably
with approximately equal potency and that are
more potent than 9 -THC in both behavioural tests and
most commonly used in the laboratory as CB 1 /CB 2
receptor binding assays. It displays high and roughly equal
receptor agonists fall essentially into one of four
affinity for both central and peripheral cannabinoid receptors
chemical groups: classical cannabinoid, nonclassical
(K i = 0.5-5.0 and 0.69-2.8 nM at CB 1 and CB 2 receptors
cannabinoid,
aminoalkylindole
and
eicosanoid
respectively).
(Table 1 and Figure 1).
Wiley et al (1995) Discriminative stimulus effects of CP 55,940 and structurally
dissimilar cannabinoids in rats. Neuropharmacology 34 669. Gatley et al (1997)
Many widely used CB 1 /CB 2 receptor agonists contain
Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole
chiral centres and generally exhibit signs of marked
AM251 to rodent brain cannabinoid receptors. Life Sci. 61 191. Griffin et al
(1998) Evaluation of cannabinoid receptor agonists and antagonists using
stereoselectivity in pharmacological assays in which
the guanosine-5´-O-(3-[ 35 S]thio)-triphosphate binding assay in rat cerebellar
the measured response is CB 1 or CB 2 receptor-
membranes. J.Pharmacol.Exp.Ther. 285 553. Thomas et al (1998) Comparative
mediated. 1,2,41 Usually, (–)- trans (6a R , 10a R ) classical
receptor binding analyses of cannabinoid agonists and antagonists.
J.Pharmacol.Exp.Ther. 285 285.
and nonclassical cannabinoids exhibit significantly
(Canadian customers require a CDSA import permit)
greater potency as cannabinoid receptor agonists
than their (+)- cis (6a S , 10a S ) enantiomers, three
notable examples of such compounds being (–)- 9 -
for example, there is evidence that endocannabinoid
tetrahydrocannabinol ( 9 -THC), (–)-11-hydroxy- 8 -
release on the one hand ameliorates spasticity in
THC-dimethylheptyl
(HU 210)
and
multiple sclerosis and inflammatory pain and on
(Table 1 and Figure 1). As to the aminoalkylindole,
the other hand contributes towards obesity in some
WIN 55,212, whilst its ( R )-(+)-isomer (WIN 55,212-2)
individuals or impairs fertility in certain women. As
exhibits significant agonist activity at both CB 1 and CB 2
a result, there is now enormous interest not only in
receptors, its ( S )-(–)-isomer (WIN 55,212-3 ) does not.
directly acting cannabinoid receptor agonists and
Indeed, when administered in vitro at concentrations
antagonists but also in compounds that can affect the
in the low micromolar range, WIN 55,212-3 has been
activity of the endocannabinoid system indirectly by
found to behave as a partial inverse agonist at CB 1
allosterically modulating endocannabinoid-induced
receptors and as a neutral CB 2 receptor antagonist. 44
activation of cannabinoid receptors or by altering the
The eicosanoid cannabinoid, anandamide, does
concentration of endocannabinoids at their receptors
not contain any chiral centres. However, some of
through effects on endocannabinoid production or
its synthetic analogues do, one example being
fate. The remainder of this review describes the
the CB 1 -selective agonist, methanandamide (see
main pharmacological actions of a number of such
next section), the ( R )-(+)-isomer of which has nine
direct and indirect cannabinoid receptor agonists
times greater affinity for CB 1 receptors than the
and antagonists. It focuses particularly on those
( S )-(–)-isomer. 45
Figure 3 | Structures of the synthetic compounds, ACEA, ACPA, ( R )-(+)-methanandamide and O-1812, and
of the endogenous compound noladin ether, all of which behave as CB 1 -selective agonists (see also Table 2)
O
O
O
Me
Cl
OH
N
N
N
H
H
H
O
Me
OH
OH
N
OH
H
O
CN
O-1812
(Bold Link Text Denotes Compounds Available From Tocris)
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