Pharmacological Actions of Cannabinoids 21Fig. 10.The structures of several CB 1 -orCB 2 -selective antagonists/inverse agonists
LY320135, AM251 and AM281 (Fig. 10). LY320135, developed by Eli Lilly, also binds
with lower affinity to CB 1 than CB 2 receptors (Table 3). However, its CB 1 affinity
is less than that of SR141716A. Moreover, at concentrations in the low micromo-
lar range, LY320135 also binds to muscarinic and 5-hydroxytryptamine (5-HT) 2
receptors (Ki<10 μM) and, at higher concentrations, to histamine H 1 receptors
(KI=12.9 μM),α 1 -andα 2 -adrenoceptors and dopamine D 1 and D 2 receptors
(Felderetal.1998).AM251andAM281arebothstructuralanaloguesofSR141716A.
They have been found to displace [^3 H]SR141716A from binding sites on mouse
cerebellar membranes with respectively three and eight times less potency than
SR141716A (Gatley et al. 1998), and both compounds have also been shown to bind
more readily to CB 1 than CB 2 receptors (Table 3). There are numerous reports that,
like SR141716A, AM251 and AM281 can attenuate in vivo or in vitro responses to
established cannabinoid receptor agonists (e.g. Cosenza et al. 2000; Gifford et al.
1997; Hájos and Freund 2002a; Lan et al. 1999a; Simoneau et al. 2001).
Although SR141716A is CB 1 -selective, it is not CB 1 -specific. Thus, results from
binding experiments indicate that whilst it may be reasonable to assume that
concentrations of this ligand in the low or mid nanomolar range will interact
mainlywiththeCB 1 receptorswhenitisappliedtotissuesthatcontainbothCB 1
and CB 2 receptors, this is not so for higher concentrations of SR141716A (Table 3).
Results obtained in vitro from functional bioassays also suggest that CB 1 receptors
are not the only pharmacological targets with which this compound can interact
at micromolar concentrations. For example, it has been found that SR141716A can
stimulate extracellular-signal-regulated protein kinase (ERK) at 1 μM (Berdyshev
et al. 2001) and antagonize anandamide-induced vasodilation in the mesenteric
arteries of CB 1 –/–mice at 1 and 5 μM (Járai et al. 1999). In addition there are
reports that at concentrations above 1 μM, SR141716A can both block and activate