36 R.G. Pertwee
adrenoceptor-mediated contractions of the mouse vas deferens (cannabidiol). In
addition, there are reports that 2-arachidonoyl glycerol and 5-HT each binds
more readily to washed human platelets in the presence of the other compound
(Maccarrone et al. 2003) and that 5-HT enhances binding ofR-(+)-WIN55212
to CB 1 receptors (Devlin and Christopoulos 2002). Importantly, cannabinoids in-
hibited 5-HT 3 receptor currents in transfected human embryonic kidney cells
with a rank order of potency, ∆^9 -THC>R-(+)-WIN55212>anandamide>JWH-
015 >LY320135>CP55940 (Barann et al. 2002), that does not correlate with their
CB 1 or CB 2 receptoraffinitiesorintrinsicactivities(Sect.3).TheIC 50 valuesofthese
ligands were 38, 104, 130, 147, 523 and 648 nM, respectively (Barann et al. 2002).
In contrast, the IC 50 values of anandamide for inhibition of kainate-activated cur-
rents in GLUA1-andGLUA3-transfectedXenopus laevisoocytes exceeded 100 μM
(Akinshola et al. 1999b). In addition, some cannabinoids, including anandamide,
methanandamide,R-(+)-WIN55212,∆^9 -THC and cannabidiol, may serve as neg-
ative modulators of delayed rectifier potassium channels (reviewed in Pertwee
2004a). There is also evidence that nanomolar concentrations of anandamide can
block low-voltage-activated (T-type) calcium channels through a mechanism that
is independent of CB 1 and CB 2 receptors and of G proteins (Chemin et al. 2001).
Evidence has also recently emerged for the presence of an allosteric site on the
cannabinoid CB 1 receptor (R. Pertwee, R. Ross and M. Price, unpublished).
4.3
Some CB 1 -andCB 2 -Independent Actions of Cannabidiol, HU-211
andOtherPhenol-ContainingCannabinoids
4.3.1NeuroprotectiveActions
Cannabinoids that contain a phenol group possess anti-oxidant (electron donor)
activity that is sufficient to protect neurons against oxidative stress associated,
for example, with glutamate-induced excitoxicity. Thus, as discussed in greater
detail elsewhere (El-Remessy et al. 2003; Fowler 2003; Hampson et al. 1998, 2000;
Marsicano et al. 2002; Mechoulam et al. 2002; Pertwee 2004b; Platt and Drysdale
2004; van der Stelt et al. 2002), this anti-oxidant activity is apparently indepen-
dent of CB 1 or CB 2 receptorsasitisexhibitedbothbytheCB 1 /CB 2 agonists
∆^9 -THC, HU-210 and CP55940, and by the non-psychoactive phytocannabinoid
cannabidiol (Fig. 1) and thecis(6aS, 10aS) enantiomer of 11-hydroxy-∆^8 -THC-
dimethylheptyl, HU-211 (Fig. 4), neither of which has significant affinity for CB 1
or CB 2 receptors (Table 4). Moreover, neurons of CB 1 –/–mice are no less well
protected from oxidative stress by phenolic cannabinoids than neurons of CB 1 +/+
mice (Marsicano et al. 2002). The neuroprotective properties of HU-211 are also
thought to stem from its ability to behave as a non-competitive antagonist at
N-methyl-d-aspartate (NMDA) receptors and to inhibit tumour necrosis factor-
αproduction (Mechoulam et al. 2002; Darlington 2003), and it is possible that
cannabidiol may also protect from glutamate-induced excitotoxicity by opposing