218 G.A. Thakur et al.
Fig. 8.Hybrid classical/non-classical (CC/NCC) cannabinoids
This new class of analogs (CC/NCC hybrids) had the added advantage of serving
as conformationally more defined three-dimensional probes for the CB 1 and CB 2
active sites than their non-classical counterparts. Receptor binding data showed
that at C-6 the equatorialβ-hydroxypropyl analog had higher affinity than itsα-
axial epimer (e.g., 29 and 30 , Fig. 8) (Drake et al. 1998; Tius et al. 1994). Further re-
finement of the CC/NCC hybrid cannabinoids was obtained by imposing restricted
rotation around this SAH pharmacophore. This was accomplished through the in-
troduction of double and triple bonds at the C2′′position of the 6β-hydroxypropyl
chain (e.g., 31 and 32 , Fig. 8).
TheaffinitydataforCB 1 /CB 2 receptorsshowninFig.8foranalogs 31 and 32 refer
to the racemic compounds. Enantiomers of 32 were recently separated using chiral
AD [amylose tris(3,5-dimethylphenylcarbamate] columns (Thakur et al. 2002) (see
Sect. 4). This very promising class of compounds encompassing four asymmetric
centers is among the most structurally complex and potent cannabinergic agents
synthesized to date.
2.4
Aminoalkylindoles
The fourth chemical class of cannabinergic ligands, the aminoalkylindoles (AAIs)
were initially developed at Sterling Winthrop as potential non-ulcerogenic analogs
of non-steroidal anti-inflammatory drugs (NSAIDs) (Bell et al. 1991) and bear no
structural relationship to the cannabinoids. These analogs also exhibited antinoci-
ceptive properties that eventually were attributed to their interactions with the