Pharmacological Actions of Cannabinoids 25Fig. 11.The structure of O-1184 and of some putative neutral cannabinoid receptor antagonists
preparation. Nor does it share the ability of the CB 1 partial agonist, O-1184, to
inhibit these contractions (Ross et al. 1999b). O-2050, a sulphonamide analogue
of∆^8 -THC with an acetylenic side chain also behaves as a neutral CB 1 receptor
antagonist in the mouse vas deferens (Martin et al. 2002). Another compound that
seemstobeaneutralCB 1 antagonist is VCHSR (Fig. 11). This is an analogue of
SR141716A that lacks hydrogen bonding capability in its C3 substituent region and
has a CB 1 Kivalue in the low nanomolar range. VCHSR (1 μM) has been found to
share the ability of SR141716A to attenuateR-(+)-WIN55212-induced inhibition of
Ca2+current in rat superior cervical ganglion neurons expressing the human CB 1
receptor but to differ from SR141716A in not affecting Ca2+current in these neu-
rons when administered by itself at 1 or 10 μM (Hurst et al. 2002; Pan et al. 1998).
In terms of the two-state model of inverse agonism (see Pertwee 2003, 2005 and
Sect. 3.3), this finding suggests that preferential binding by SR141716A to the “off”
state of the CB 1 receptor is determined by hydrogen bond formation between the
C3 substituent of this molecule and the receptor. Further experiments are required
to establish whether putative neutral antagonists, such as NESS 0327, O-2654 and
O-2050, resemble SR141716A (Sect. 3.3) in exhibiting inverse agonist properties at
concentrations above those at which they behave as neutral antagonists.