34 R.G. Pertwee
One cannabidiol analogue has been found to behave as a selective abnormal-
cannabidiol receptor antagonist. This is O-1918 (Fig. 12), which lacks detectable
affinity for CB 1 and CB 2 receptors and, at concentrations of 1 to 30 μM, opposes
abnormal-cannabidiol and anandamide-induced relaxations of rat arterial seg-
ments and does not reduce vasomotor tone when administered alone (Offertáler
et al. 2003). It has also been found to attenuate abnormal-cannabidiol-induced
hypotension in anaesthetized mice at doses not affecting hypotension induced by
the CB 1 /CB 2 receptor agonist HU -210 (Offertáler et al. 2003). Cannabidiol also
behaves as a selective abnormal-cannabidiol receptor antagonist in both the rat
mesenteric arterial bed and the anaesthetized mouse (Járai et al. 1999). However, in
contrast to O-1918, it has been found to share the ability of abnormal-cannabidiol
to relax rat precontracted mesenteric arterial segments (Offertáler et al. 2003).
It is likely that there are two sub-types of abnormal-cannabidiol-sensitive re-
ceptor in mesenteric arteries capable of mediating a relaxant effect, one expressed
by endothelial cells and the second by non-endothelial cells (reviewed in Pertwee
2004a). Activation of the endothelial receptor appears to open large conductance
calcium-activated potassium (BKCa) channels, whereas the non-endothelial recep-
tor seems to signal mainly through inhibition of L-type calcium channels (Begg
et al. 2003; Ho and Hiley 2003; Járai et al. 1999; Offertáler et al. 2003). There is
also now evidence that abnormal-cannabidiol receptors can mediate stimulation
of the migration of vascular endothelial cells through a mechanism that is Gi/o
protein-coupled and susceptible to antagonism by O-1918 (Mo et al. 2004).
Microglial Cells
Experiments with the mouse microglial cell line BV-2 (Walter et al. 2003) have
provided evidence that microglial cells express receptors that have certain prop-
erties in common with the putative vascular abnormal-cannabidiol receptor dis-
cussed above. These include susceptibility to activation by abnormal-cannabidiol
and anandamide and to blockade by O-1918 and lack of sensitivity to activation
by∆^9 -THC, at least at concentrations below 3 μM. When activated, these pro-
posed abnormal-cannabidiol-sensitive receptors appear to trigger chemokinetic
and chemotaxic migration of microglial cells. Such migration can also be in-
duced by 2-arachidonoyl glycerol (EC 50 =25 nM). This endocannabinoid seems to
act through both microglial CB 2 receptors and microglial abnormal-cannabidiol-
sensitive receptors, since it is antagonized by cannabidiol at 300 nM and by
SR144528 at 30 nM but not by 30 nM SR141716A (Walter et al. 2003). Indeed,
it has been proposed that microglial CB 2 receptors and abnormal-cannabidiol
receptors interact in a synergistic manner when triggering the migration of mi-
croglial cells (Walter et al. 2003). This could explain why the CB 1 -selective agonist
ACPA (Sect. 3.1), induces microglial cell migration at concentrations well below
those at which it has been reported to bind to CB 2 receptors, as this compound
appears to induce migration by acting on both abnormal-cannabidiol-sensitive
receptors and CB 2 receptors (Franklin and Stella 2003). By itself, cannabidiol be-
haves as a weak partial agonist, producing a slight enhancement of basal migration
(EC 50 =250 nM) (Walter et al. 2003). Microglial cells are thought to migrate towards