agonists include the GlaxoSmithKline compound
GW 405833, which behaves as a potent partial
GW 405833, Potent CB 2
agonist at the CB 2 receptor, 67 and HU 308, AM 1241
and the Merck Frosst compounds L-759,633 and
Partial Agonist
O
L-759,656. 1,2 Interestingly, AM 1241 may be a
“protean agonist” as it has been reported to behave
Cat. No. 2374
N
as an agonist in tissues in which CB 2 receptors
MeO
Me
N
Table 2 | K i values of CB 1 - and CB 2 -selective
ligands for the in vitro displacement of
O
[ 3 H]CP 55,940 or [ 3 H]HU 243 from CB 1 - and
Cl
Cl
CB 2 -specific binding sites
GW 405833 is a highly potent and selective CB 2 receptor
CB 1
CB 2
partial agonist. In a functional assay using human
Ligand
K i value
K i value
Reference
recombinant CB 2 receptors, the compound displays an
(nM)
(nM)
EC 50 value of 0.65 nM and a maximum inhibition of 44.6%
CB 1 -selective agonists
at 300 nM. It binds with high affinity to both human and rat
1.4 a,b
> 2000 a,b
50
CB 2 receptors and displays ~ 1200-fold selectivity over CB 1
5.29 a,b
195 c
62
(K i values are 3.92 and 4772 nM for human recombinant
CB 2 and CB 1 receptors respectively). GW 405833 produces
O-1812
3.4 a
3870 a
49
potent antihyperalgesic effects in several rodent models of
2.2 a,b
715 a,b
50
pain.
21.2 a
> 3000 d
52
Clayton et al (2002) CB1 and CB2 cannabinoid receptors are implicated in
17.9 a,b
868 c
62
inflammatory pain. Pain 96 253. Valenzano et al (2005) Pharmacological
and pharmacokinetic characterization of the cannabinoid receptor 2 agonist,
20 a,b
815 c
63
GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia
28.3 a
868 c
64
and catalepsy. Neuropharmacology 48 658.
CB 1 -selective antagonists/inverse agonists
SR141716A
1.8 c
514 c
55
are naturally expressed but not in tissues in which
1.98 a
> 1000 a
56
5.6
> 1000
56
CB 2 receptors have been inserted genetically and
11.8
13200
57
are therefore presumably overexpressed. 73 The
11.8
973
58
structures of JWH 133, JWH 015, HU 308, AM 1241
12.3
702
59
and GW 405833 are shown in Figure 4 and their
12 a
4200 c
60
CB 1 and CB 2 binding properties are summarised in
7.49 a
2290 c
61
Table 2.
141
14900
57
Selective CB 1 Receptor Antagonists/
CB 2 -selective agonists
Inverse Agonists
AM 1241
280 a
3.4 c
65
The first of these to be developed was the
677 a
3.4
66
diarylpyrazole, SR141716A. 56 This is a highly
4772
3.92
67
potent and selective CB 1 receptor ligand that readily
273 a
3.6 a
prevents or reverses CB 1 -mediated effects both in
383
13.8
59
vitro and in vivo . 1,2,41 Other notable CB 1 -selective
HU 308
> 10000 a,e
22.7 d,e
68
antagonists are AM 251 and AM 281, both developed
CB 2 -selective antagonists/inverse agonists
by Dr Alexandros Makriyannis, and LY 320135 which
SR144528
70 c
0.28 c
55
has less affinity for CB 1 receptors than SR141716A,
305 a
0.30 a
69
AM 251 or AM 281 and at concentrations in the
437
0.60
69
low micromolar range also binds to muscarinic and
50.3
1.99
70
5-hydroxytryptamine (5-HT 2 ) receptors. 1,2,41
> 10000
5.6
71
5152
31.2
71
As detailed elsewhere, 2,74 there is convincing
evidence that SR141716A, AM 251, AM 281 and
(Bold Text Denotes Compounds Available From Tocris)
LY 320135 are not “neutral” antagonists. Thus, as
ACEA, arachidonyl-2´-chloroethylamide; ACPA, arachidonylcyclopropylamide.
well as attenuating effects of CB 1 receptor agonists,
a Binding to rat cannabinoid receptors in transfected cells or in brain (mainly CB 1 )
they can by themselves elicit responses in some
or spleen tissue (mainly CB 2 ).
b With phenylmethylsulphonyl fluoride in order to inhibit enzymic hydrolysis.
CB 1 receptor-containing tissues that are opposite in
c Binding to mouse brain (mainly CB 1 ) or spleen tissue (mainly CB 2 ).
direction from those elicited by CB 1 receptor agonists.
d Species unspecified.
Whilst
such
“inverse
cannabimimetic
effects”
All other data from experiments with human cannabinoid receptors.
may in some instances be attributable to a direct
antagonism of responses evoked at CB 1 receptors
e Displacement of [ 3 H]HU 243 from CB 1 - and CB 2 -specific binding sites;
[ 3 H]CP 55,940 was used in all other experiments.
by released endocannabinoids, there is evidence
that this is not always the underlying mechanism and
See Figures 3 to 5 for the structures of the compounds listed in this table.
that SR141716A, AM 251, AM 281 and LY 320135
Page 5