216 G.A. Thakur et al.
Fig. 6.Cannabinoid analogs possessing a northern aliphatic hydroxyl (NAH) group
an unfavorable orientation of a C-9 hydroxyl or hydroxymethyl substituent can
seriously interfere with this ligand’s ability to interact with cannabinoid receptors.
Based on the relative configuration at the C-9 position, the HHC encompasses two
types of isomers (9αand 9β). Although both isomers are biologically active, the
β-epimers in which the C-9 hydroxyl or hydroxymethyl group is equatorial (e.g.,
22 and 23 , Fig. 6) have been shown to be more potent than theα-axial isomers
(Devane et al. 1992a; Wilson et al. 1976; Yan et al. 1994). The preference for the 9β
relative configuration has been used for the design and synthesis of high-affinity
photoactivatable probes for the cannabinoid receptors (e.g., AM1708,70,Fig. 19)
(Khanolkar et al. 2000). Presence of a C-9 carbonyl group encompassed in nabilone
( 24 , Fig. 6) is also known to significantly enhance cannabinergic activity (Archer et
al. 1986). Although the nature of the substituent at the northern end of the classical
cannabinoid structure has an effect on the ligands’ potencies, these effects have
not yet been fully investigated. Thus, 9-nor-∆^9 -THC, a molecule that lacks a C-9
substituent, exhibits significant cannabinoid activity (Martin et al. 1975).
2.2
Non-classical Cannabinoids
A second class of cannabinergic ligands possessing close similarity with CCs was
developed at Pfizer in an effort to simplify the CC structure, while maintaining
or improving biological activity (Johnson and Melvin 1986; Little et al. 1988).
This group of compounds, generally designated as non-classical cannabinoids
(NCCs), includes AC-bicyclic (e.g., 25 and 26 , Fig. 7) and ACD-tricyclic (e.g., 27 ,
Fig. 7) ligands lacking the pyran B-ring of CCs. Of these the best known is CP-