24 R.G. Pertwee
SR144528 has greater inverse intrinsic activity than AM630. If this interpretation
of the data is valid, it is of course an indication that just as the intrinsic activities
of CB 1 and CB 2 receptor agonists can vary from compound to compound, so too
the (inverse) intrinsic activities of cannabinoid receptor inverse agonists will not
be the same for all such ligands.
Whilst there is little doubt that the presence of CB 1 receptors is a prerequisite
for the production by SR141716A of many of its inverse cannabimimetic effects, it
is noteworthy that this compound has been found to produce an effect on GTPγS
binding to whole brain membranes obtained from CB 1 –/–mice (enhancement) op-
posite to that produced byR-(+)-WIN55212 or anandamide (inhibition) (Breivogel
et al. 2001). This finding supports the hypothesis that at least some apparent inverse
effects of SR141716A may be induced at sites that are not located on CB 1 recep-
tors (Sim-Selley et al. 2001). Indeed, it is already known that SR141716A not only
binds to CB 2 receptors at concentrations in the high nanomolar range and above
(Table 3) but also behaves as a CB 2 receptor inverse agonist at such concentrations,
as measured by inhibition of [^35 S]GTPγS binding to hCB 2 receptors on CHO cell
membranes (MacLennan et al. 1998).
3.4 NeutralAntagonismatCannabinoidReceptors
An important recent pharmacological objective has been the development of
cannabinoid receptor ligands for CB 1 and CB 2 receptors that completely lack both
inverse agonist and agonist properties (neutral antagonists). One cannabinoid
receptor ligand that comes close to being a neutral antagonist is 6′-azidohex-2′-
yne-∆^8 -THC (O-1184; Fig. 11 and Table 4), as this behaves as a high-affinity, low-
efficacy agonist at CB 1 receptors and as a high-affinity, low-efficacy inverse agonist
at CB 2 receptors,andasitproducespotentantagonismofR-(+)-WIN55212 and
CP55940 in the myenteric plexus–longitudinal muscle preparation of guinea-pig
small intestine (Ross et al. 1998, 1999b). More recently, an analogue of SR141716A,
NESS 0327, has been developed that behaves as a neutral CB 1 receptor antagonist
and is markedly more potent and CB 1 -selective than SR141716A (Table 3) (Ruiu
et al. 2003). This was achieved by reducing the molecule’s flexibility through the
introduction of a seven-membered ring (Fig. 11). Evidence has also emerged that
insertion of a 6′′-azidohex-2′′-yne side chain into cannabidiol (Fig. 1) converts
this molecule into a neutral cannabinoid receptor antagonist (Thomas et al. 2004).
This compound, O-2654 (Fig. 11), has markedly higher affinity than cannabidiol
for CB 1 receptors and antagonizesR-(+)-WIN55212-induced inhibition of elec-
trically evoked contractions of the mouse isolated vas deferens in a competitive,
surmountable manner with aKB(85.7 nM) that is close to itsKifor displacing
[^3 H]CP55940 from CB 1 receptors (114 nM). The conclusion that O-2654 may be
a neutral antagonist is based on the observation that at concentrations of up to
10 μM, it exhibits no detectable CB 1 agonist or inverse agonist properties in the
mouse isolated vas deferens. Thus, unlike SR141716A (Pertwee et al. 1996b), O-
2654 does not increase the amplitude of electrically evoked contractions of this