22 R.G. Pertwee
transient receptor potential vanilloid type 1 (TRPV1) receptors (previously known
as VR1 receptors), suggesting that it may be a TRPV1 receptor partial agonist (De
Petrocellis et al. 2001a; Zygmunt et al. 1999), block adenosine A 1 receptors (as can
AM251) (Savinainen et al. 2003), oppose vasorelaxation induced by acetylcholine
in ring preparations of rabbit preconstricted isolated superior mesenteric arteries
(Chaytor et al. 1999) and by bradykinin in human preconstricted myometrial small
arteries (Kenny et al. 2002), and block potassium and L-type calcium channels in
rat isolated mesenteric arteries (White and Hiley 1998) and gap junctions between
COS-7 cells (Chaytor et al. 1999).
Unexpectedly, in spite of the close similarity between the structures of AM251,
AM281 and SR141716A, differences in their pharmacological profiles have been
detected in vitro in experiments with cardiovascular tissue (reviewed in Pertwee
2004a). It has also been found that the ability ofR-(+)-WIN55212 to reduce gluta-
matergic transmission is opposed by 1 μM SR141716A in CB 1 –/–mouse hippocam-
pal slices but not by 2 μM AM251 in rat hippocampal slices (Hájos and Freund
2002a; Hájos et al. 2001).
3.2.2 Selective CB 2 ReceptorAntagonists........................
The most important selective CB 2 receptor antagonists are the diarylpyrazole
SR144528 and the aminoalkylindole 6-iodopravadoline (AM630) (Fig. 10). Both
bind with markedly higher affinity to CB 2 than CB 1 receptors (Table 3) and prevent
orreverseinvitroeffectsmediatedbyCB 2 receptors (Portier et al. 1999; Rinaldi-
Carmona et al. 1998; Ross et al. 1999a). Evidence also exists that on the one hand,
SR144528 lacks significant affinity for a wide range of established non-cannabinoid
receptors (Rinaldi-Carmona et al. 1998), and on the other hand it is an antagonist
for a putative CB 2 -like receptor that is activated by palmitoylethanolamide, a ligand
that does not have significant CB 2 receptor affinity (Sect. 4.1.3). Interestingly, it has
proved possible to develop diarylpyrazoles with even greater CB 2 selectivity and
affinity than SR144528 (Mussinu et al. 2003). This has been achieved by making
these molecules less flexible.
Turning now to AM630, particularly with regard to its behaviour at the CB 1
receptor, there are several reports that when administered at concentrations in
the micromolar range, it exhibits the mixed agonist-antagonist properties typical
of a weak partial agonist for this receptor (reviewed in Pertwee 1999a). However,
there are also reports that AM630 can behave as a CB 1 receptor inverse agonist
(Landsman et al. 1998; Vásquez et al. 2003).
3.3 InverseAgonismatCannabinoidReceptors
There is good evidence that when administered by itself in vivo or in vitro,
SR141716A is capable of producing inverse cannabimimetic effects, i.e. effects