Receptors for Abnormal Cannabidiol

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Cardiovascular System

There is evidence, mainly from in vitro experiments with rat or mouse phenylephrine- or methoxamine-precontracted buffer-perfused isolated mesenteric arterial beds or isolated mesenteric arterial segments, for the presence in these tissues of non-CB1, non-CB2 receptors with which anandamide and methanandamide can interact to induce a relaxant effect (reviewed in Howlett et al. 2002; Pertwee 2004a; Wiley and Martin 2002). There are several reasons for believing that these are not CB1 or CB2 receptors. First, relaxation is not induced in rat precontracted mesen-teric arterial beds by 2-arachidonoyl glycerol or by established non-eicosanoid cannabinoid receptor agonists such as 49-THC or £-(+)-WIN55212 (Wagner et al. 1999) but is induced in rat and mouse precontracted mesenteric arterial beds or rat precontracted mesenteric arterial segments by two cannabidiol analogues, abnormal-cannabidiol and 0-1602 (Fig. 12), neither of which exhibits significant affinity for CB1 receptors (Ho and Hiley 2003; Jarai et al. 1999; Offertaler et al. 2003; Showalter et al. 1996). Second, anandamide, methanandamide and abnormal-cannabidiol also relax precontracted buffer-perfused mesenteric arterial beds of CB1-/- knockout or CB1-/-/CB2-/- double-knockout C57BL6J mice (Jarai et al. 1999). Third, the CB1-selective antagonist AM281 (1 ^M) and the CB2-selective antagonist AM630 (10 ^M) do not attenuate abnormal-cannabidiol-induced relaxations of rat precontracted mesenteric arterial segments (Ho and Hiley 2003). Although SR141716A has been found to oppose the vasorelaxant effects of abnormal-cannabidiol, methanandamide and anandamide in rat or mouse precontracted mesenteric arterial beds or segments, this is generally with a potency lower than expected from its affinity for CB1 receptors (Ho and Hiley 2003; Jarai et al. 1999). Negative results obtained with capsaicin and capsazepine also make it unlikely that the putative "abnormal-cannabidiol" receptor is a TRPV1 receptor (Ho and Hiley 2003; Jarai et al. 1999; Offertaler et al. 2003).

Abnormal cannabidiol .

0-1602

Abnormal cannabidiol .

0-1602

3 0-1918

Fig. 12. The structures of abnormal cannabidiol, 0-1602 and 0-1918

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 CB1 and CB2 receptors and, at concentrations of 1 to 30 ^M, opposes abnormal-cannabidiol and anandamide-induced relaxations of rat arterial segments and does not reduce vasomotor tone when administered alone (Offertaler 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 CB1/CB2 receptor agonist HU -210 (Offertaler et al. 2003). Cannabidiol also behaves as a selective abnormal-cannabidiol receptor antagonist in both the rat mesenteric arterial bed and the anaesthetized mouse (Jarai 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 (Offertaler et al. 2003).

It is likely that there are two sub-types of abnormal-cannabidiol-sensitive receptor 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 receptor seems to signal mainly through inhibition of L-type calcium channels (Begg et al. 2003; Ho and Hiley 2003; Jarai et al. 1999; Offertaler 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 properties in common with the putative vascular abnormal-cannabidiol receptor discussed above. These include susceptibility to activation by abnormal-cannabidiol and anandamide and to blockade by O-1918 and lack of sensitivity to activation by 49-THC, at least at concentrations below 3 ^M. When activated, these proposed abnormal-cannabidiol-sensitive receptors appear to trigger chemokinetic and chemotaxic migration of microglial cells. Such migration can also be induced by 2-arachidonoyl glycerol (EC50 = 25 nM). This endocannabinoid seems to act through both microglial CB2 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 CB2 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 CBi-selective agonist ACPA (Sect. 3.1), induces microglial cell migration at concentrations well below those at which it has been reported to bind to CB2 receptors, as this compound appears to induce migration by acting on both abnormal-cannabidiol-sensitive receptors and CB2 receptors (Franklin and Stella 2003). By itself, cannabidiol behaves as a weak partial agonist, producing a slight enhancement of basal migration (EC50 = 250 nM) (Walter et al. 2003). Microglial cells are thought to migrate towards neuroinflammatory lesion sites and to release proinflammatory cytokines and cytotoxic agents at these sites. Consequently, since Walter et al. (2003) also obtained evidence that the production of 2-arachidonoyl glycerol by microglial cells can be increased by a pathological stimulus, it may be that a CB2 receptor antagonist and/or an antagonist of the putative abnormal-cannabidiol receptor could come to play a part in the clinical management of neuroinflammation. More recently, evidence has emerged that BV-2 microglial cells express non-CBi, non-CB2, non-CB2-like, non-TRPV1, non-abnormal-cannabidiol G/Go-coupled-receptors upon which the endogenous fatty acid amide palmitoylethanolamide can act at concentrations in the low nanomolar range to potentiate anandamide- but not 2-arachidonoyl glycerol-induced migration of these cells (Franklin et al. 2003). There is also evidence for the presence in rat migroglial cells of non-CB1, non-CB2, pertussis toxin-insensitive receptors with which R-(+)- but not S-(-)-WIN55212 can interact to inhibit lipopolysaccharide-induced release of the proinflammatory cytokine tumour necrosis factor-« (Facchinetti et al. 2003).

Mouse Vas Deferens

A finding that abnormal-cannabidiol and cannabidiol can attenuate phenylephrine-induced contractions of the mouse isolated vas deferens points to the presence of abnormal-cannabidiol-sensitive receptors in the smooth muscle cells of this tissue (Pertwee et al. 2002; Thomas et al. 2004). Cannabidiol also decreases methoxamine and noradrenaline-induced contractions of the mouse vas deferens and antagonizes phenylephrine and noradrenaline in an insurmountable manner (Pertwee et al. 2002). It may be, therefore, that cannabidiol, and possibly also abnormal-cannabidiol, are negative allosteric modulators of the a1 -adrenoceptor.

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