230 G.A. Thakur et al.
groups, which may destabilize their interactions with the receptor. Introduction of
a methyl group orgem-dimethyl group at the C-2 position results in metabolically
stable analogs with concomitant increase in CB 1 affinity as in the case of C-1′
methylation (Adams et al. 1995b; Goutopoulos et al. 2001)
n-Pentyl Group Tail ModificationsAlthough there is no apparent structural sim-
ilarity between the classical cannabinoids and anandamide, there is considerable
evidence suggesting that these two classes of cannabimimetic agents bind simi-
larly to the CB 1 active site (Barnett-Norris et al. 2002; A. Makriyannis and C. Li,
unpublished results). There is ample chemical and computational evidence indi-
cating that arachidonic acid, the parent fatty acid of anandamide, favors a bent
or looped conformation in which the carbonyl group is proximal to the C14–
C15 olefinic bond. The chemical evidence for such a conformation includes the
highly regiospecific intramolecular epoxidation of arachidonoyl peracid (Corey et
al. 1984) and the facile macrolactonization of C20 hydroxyl methyl arachidonate
(Corey et al. 1983). These experimental results are corroborated by molecular dy-
namics calculations (Rich 1993) that indicate that indeed a bent conformation is
thermodynamically favorable. In the case of arachidonoylethanolamides, molecu-
lar modeling studies (Barnett-Norris et al. 1998, 2002; Rich 1993) have shown that
anandamide and other fatty acid ethanolamides and esters also prefer a hairpin
conformation. Additional data (Thomas et al. 1996; Tong et al. 1998) indicate that
such a bent conformation is capable of mimicking the three-dimensional structure
of tetrahydro- and hexahydrocannabinols.
However,itisunclearwhetherthehairpinconformationisalsotheconformation
at the CB 1 receptor active site. Recent biophysical work on the conformational
properties of anandamide in the membrane provide evidence for a more extended
conformation for the C20 chain (A. Makriyannis and X. Tian, unpublished results)
and suggest alternative CB 1 pharmacophoric conformations.
As discussed earlier, the SAR for the side chain of classical cannabinoids has
been studied extensively, and it is known that a 1′,1′-dimethylheptyl (DMH) sub-
stituent generally leads to optimal potency. There is also evidence that classical
cannabinoids and anandamides interact with similar residues at the CB 1 binding
sites. This it was postulated that a similar substitution in anandamide should result
Fig. 17.Tail modified analogs of anandamide