Structural Requirements for Cannabinoid Receptor Probes 217Fig. 7.Non-classical cannabinoid receptor ligands
55,940 ( 25 ) a crystalline ligand exhibiting high affinity for both CB 1 and CB 2
as well as a high degree of stereoselectivity. [^3 H]CP-55,940, the tritiated analog,
was the key compound that led to the discovery of CB 1 (Devane et al. 1988).
This class of compounds shares some of the key pharmacophores of the CCs,
namely the phenolic OH, the side chain, and the northern aliphatic hydroxyl
groups. Additionally, it encompasses an hydroxypropyl chain on the cyclohexyl
ring contiguous and trans to the aromatic phenolic group as with CP-55,940. This
important new pharmacophore was designated as the southern aliphatic hydroxyl
group (SAH) (Makriyannis and Rapaka 1990) and has been subjected to extensive
investigation by the Makriyannis and Tius groups (Chu et al. 2003; Drake et al.
1998; Harrington et al. 2000; Tius et al. 1997, 1994).
The recently introduced ligand HU-308 ( 28 , Fig. 7), which has the opposite
absolute configuration from all other CC and NCC analogs, is another example
of bicyclic cannabinoid receptor ligands (Hanus et al. 1999) and exhibits a high
degree of CB 2 selectivity.
2.3
CC/NCC Hybrid Cannabinoids
The southern aliphatic hydroxyl (SAH) pharmacophore is absent in the naturally
occurring cannabinoids. To study more precisely the stereochemical requirements
of this new pharmacophore, Makriyannis and co-workers designed a group of
hybrid ligands that incorporated all of the structural features of both classical and
non-classical cannabinoids (Drake et al. 1998; Tius et al. 1995, 1994).