16 R.G. Pertwee
Fig. 8.The structures of eight structural analogues of anandamide
Many cannabinoid receptor agonists exhibit marked stereoselectivity in phar-
macological assays, reflecting the presence of chiral centres in these compounds
(reviewed in Howlett et al. 2002). Classical and nonclassical cannabinoids with the
same absolute stereochemistry as (–)-∆^9 -THC at 6a and 10a,trans(6aR, 10aR), are
more active than theircis(6aS, 10aS)enantiomers,whilstR-(+)-WIN55212 is more
active thanS-(–)-WIN55212. Although anandamide does not contain any chiral
centres, some of its synthetic analogues do. One of these is methanandamide, the
R-(+)-isomer of which exhibits nine times higher affinity for CB 1 receptors than
theS-(–)-isomer (Abadji et al. 1994).
Several cannabinoid receptor agonists bind more or less equally well to CB 1
and CB 2 receptors (Table 2), although they do exhibit different relative intrinsic
activities at these receptors. Among these are HU-210, CP55940,R-(+)-WIN55212,
(–)-∆^9 -THC, anandamide and 2-arachidonoyl glycerol (reviewed in Howlett et al.
2002; Pertwee 1999a).
- HU-210 has particularly high affinity for both CB 1 and CB 2 receptors. It also
exhibits high relative intrinsic activities at these receptors. Indeed, it is remark-
ably potent as a cannabinoid receptor agonist and exhibits an exceptionally long
duration of action in vivo. The marked affinity and efficacy that HU-210 shows
at cannabinoid receptors is due largely to the replacement of the pentyl side
chain of∆^8 -THC with a dimethylheptyl group.
- CP55940 andR-(+)-WIN55212 have CB 1 and CB 2 relative intrinsic activities of
the same order as those of HU-210 and, although they have lower CB 1 and CB 2
affinities than HU-210, are still reasonably potent as they bind to these receptors
at concentrations in the low nanomolar range.