18 R.G. Pertwee
Fig. 9.The structures of BAY 38-7271, JTE-907, ajulemic acid and O-1057
activity of virodhamine matched that of anandamide which, however, behaved as
a full agonist in this investigation, suggesting that the CB 2 expression level of the
cell line used may have been rather high. In contrast, the CB 1 intrinsic activity
of virodhamine was less than that of anandamide, and indeed it was found that
virodhamine could attenuate anandamide-induced activation of CB 1 receptors. No
binding data are yet available for virodhamine.
Turning now to potent cannabinoid receptor agonists that interact more readily
with CB 1 or CB 2 receptors, a number of these have been developed. The starting
point for all current CB 1 -selective agonists has been anandamide. Thus, results
from binding experiments have shown that it is possible to enhance the marginal
CB 1 selectivity exhibited by anandamide by replacing a hydrogen atom on the
1 ′or2carbonwithamethylgrouptoformR-(+)-methanandamide or O-689
(Fig. 8) (Abadji et al. 1994; Showalter et al. 1996). As well as increasing CB 1 se-
lectivity, insertion of a methyl group on the 1′or 2 carbon of anandamide in-
creases resistance to the hydrolytic action of fatty acid amide hydrolase (FAAH)
(Abadji et al. 1994; Adams et al. 1995). Anandamide analogues that exhibit par-
ticularly marked CB 1 -selectivity in binding assays are ACEA, ACPA and a cyano
analogue of methanandamide (O-1812) (Table 2; Fig. 8). All three behave as potent
CB 1 receptor agonists (Di Marzo et al. 2001; Hillard et al. 1999). O-1812 appears
to lack significant susceptibility to hydrolysis by FAAH, presumably because it
resemblesR-(+)-methanandamide in having a methyl group attached to its 1′-
carbon. ACEA and ACPA, which do not have the 1′-carbon methyl substituent of
R-(+)-methanandamide, show no sign of reduced susceptibility to enzymic hy-