Cannabinoid Receptor Ligands
neuronal transporters of dopamine, noradrenaline
JTE 907, CB 2 -Selective
and 5-hydroxytryptamine (Table 3), and that there are
Inverse Agonist
a number of less sensitive pharmacological targets
for ∆ 9 -THC and/or for certain other cannabinoid
O
receptor agonists. These targets, which only seem to
Cat. No. 2479
N
O
H
respond to cannabinoid concentrations above 1 µ M,
MeO
N
O
O
H
include L-type Ca 2+ and shaker Kv1.2 K + channels,
O
PPAR γ and TRPA1 receptors, putative non-CB 1 ,
non-CB 2 , non-TRPV1 neuronal receptors in the small
JTE 907 is a highly selective CB 2 receptor inverse agonist.
intestine, sites on muscarinic M 1 and M 4 receptors
It binds with high affinity to rat, mouse and human CB 2
and on glutamate GLU A1 and GLU A3 receptors,
receptors (K i values are 0.38, 1.55 and 35.9 nM respectively)
and produces anti-inflammatory effects in vivo .
and sites at gap junctions between cells. 2,86,88,94,95
Anandamide and methanandamide, but not ∆ 9 -THC,
Iwamura et al (2001) In vitro and in vivo pharmacological characterization of
JTE-907, a novel selective ligand for cannabinoid CB 2 receptor. J.Pharmacol.
WIN 55,212-2 or 2-arachidonylglycerol , also behave
Exp.Ther. 296 420. Ueda et al (2005) Involvement of cannabinoid CB 2 receptor-
as agonists for the putative abnormal-cannabidiol
mediated response and efficacy of cannabinoid CB 2 receptor inverse agonist,
JTE-907, in cutaneous inflammation in mice. Eur.J.Pharmacol. 520 164.
(abnormal-CBD) receptor 2,88,96 (see also section on
Maekawa et al (2006) The cannabinoid CB 2 receptor inverse agonist JTE-907
other notable ligands).
suppresses spontaneous itch-associated responses of NC mice, a model of
atopic dermatitis. Eur.J.Pharmacol. 542 179.
The CB 1 receptor antagonists/inverse agonists,
SR141716A and AM 251, can also interact with non-
[ 3 H]CP 55,940, [ 3 H]WIN 55,212-2 and [ 3 H]HU 243
CB 1 , non-CB 2 targets, albeit only at concentrations
are 0.07 to 4 nM, 1.9 to 16.2 nM and 0.045 nM
that lie in the micromolar range and hence above
respectively at CB 1 receptors and 0.2 to 7.4 nM, 2.1 to
concentrations at which these ligands are capable of
3.8 nM and 0.061 nM respectively at CB 2 receptors. 2,41
producing significant CB 1 receptor antagonism. Thus
Thus [ 3 H]HU 243, which is structurally very similar to
for example, as also discussed elsewhere, 74,88 there
HU 210 (Figure 1), has particularly high affinity for
are reports that at micromolar concentrations:
these receptors. Radiolabelled ligands have also
been developed as potential probes for human single
photon emission computed tomography (SPECT) or
receptor activation,
positron emission tomography (PET) experiments.
These are 123 I labelled analogues of AM 251
channels,
(CB 1 K d = 0.23 to 0.62 nM) and AM 281 81-83 and an
18 F-labelled analogue of SR141716A (SR144385). 84
Particularly promising results have been obtained
Ca 2+ -activated (BK) K + channels, ATP-sensitive
from animal experiments with [ 123 I]AM 281. 82,85
K + channels and sites at gap junctions between
cells,
Additional Pharmacological Targets
for CB 1 and CB 2 Receptor Ligands
abnormal-CBD receptors on mesenteric arteries
It
is
now
generally
accepted
that
some
cannabinoid receptor agonists are reasonably
potent at activating the TRPV1 (vanilloid VR1)
AM 630, Competitive
receptor (Table 3). These include eicosanoids
such as anandamide, methanandamide, ACEA,
CB 2 Antagonist
O
and
some
metabolites,
and the putative endocannabinoid, OLDA, but
Cat. No. 1120
exclude 2-Arachidonylglycerol and also classical,
I
N
Me
OMe
nonclassical
and
aminoalkylindole
cannabinoid
N
WIN 55,212-2. 2,5,88,92,93
O
A number of other non-CB 1 , non-CB 2 pharmacological
targetsforsomeCB 1 /CB 2 receptoragonistshavebeen
AM 630 is a CB 2 receptor antagonist (K i = 31.2 nM) that is
proposed, including several that appear to respond to
165-fold selective over CB 1 . The ligand displays inverse
agonist concentrations of 1 micromolar or less (Table
agonist properties in CHO cells expressing CB 2 receptors
3), and hence to possess sensitivity to these ligands
and behaves as a weak partial/inverse agonist at CB 1
of the same order as that exhibited by CB 1 or CB 2
receptors.
receptors. Thus, for example, anandamide interacts
Hosohata et al (1997) AM630 is a competitive cannabinoid receptor antagonist
at submicromolar concentrations with several types
in the guinea pig brain. Life Sci. 61 PL115. Hosohata et al (1997) AM630
antagonism of cannabinoid-stimulated [ 35 S]GTP γ S binding in the mouse brain.
of ligand-gated and voltage-gated ion channels,
Eur.J.Pharmacol. 321 R1. Landsman et al (1998) AM630 is an inverse agonist
some (but not all) of which are also sensitive
at the human cannabinoid CB 1 receptor. Life Sci. 62 PL109. Ross et al (1999)
Agonist-inverse agonist characterization at CB 1 and CB 2 cannabinoid receptors
to
∆ 9 -THC,
of L759633, L759656 and AM630. Br.J.Pharmacol. 126 665.
WIN 55,212-2 and/or JWH 015 (Table 3). There is
(Sold with the permission of the University of Connecticut)
evidence too that ∆ 9 -THC also interacts potently with
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