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
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
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
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
(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.
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