250 P.H. Reggio
1.1
Cannabinoid Receptor Agonists
The CB 1 receptor transduces signals in response to CNS-active constituents of
Cannabis sativa, such as the classical cannabinoid (CB) (–)-trans-∆^9 -tetrahydro-
cannabinol [(–)-∆^9 -THC ( 1 )] and to three other structural classes of ligands, the
non-classicalCBstypifiedby(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phe-
nyl]-4-(3-hydroxypropyl) cyclohexan-1-ol [CP-55,940 ( 2 )] (Devane et al. 1988;
Melvin et al. 1995), the aminoalkylindoles (AAIs) typified byR-2,3-dihydro-5-
methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-ylmethanone [WIN55,212-2 ( 3 )] (Compton et al. 1992; D’Ambra et al. 1992;
Ward et al. 1991), and the endogenous CBs. The non-classical CBs clearly share
many structural features with the classical CBs, e.g., a phenolic hydroxyl at C-1
(C2′), and alkyl side chain at C-3 (C-4′), as well as the ability to adopt the same
orientation of the carbocyclic ring as that in classical CBs (Reggio et al. 1993).
The AAIs, on the other hand, bear no obvious structural similarities with the
classical/non-classical CBs.
The first endogenous CB was isolated from porcine brain by Mechoulam and
co-workers (Devane et al. 1992). The endogenous CB ligands are unsaturated