CCNCC 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).

Fig. 8. Hybrid classical/non-classical (CC/NCC) cannabinoids

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 CB1 and CB2 active sites than their non-classical counterparts. Receptor binding data showed that at C-6 the equatorial ^3-hydroxypropyl analog had higher affinity than its a-axialepimer (e.g., 29 and 30, Fig. 8) (Drake et al. 1998;Tiuset al. 1994). Further refinement of the CC/NCC hybrid cannabinoids was obtained by imposing restricted rotation around this SAH pharmacophore. This was accomplished through the introduction of double and triple bonds at the C2" position of the 6^-hydroxypropyl chain (e.g., 31 and 32, Fig. 8).

The affinity data for CB1 /CB2 receptors shown in Fig. 8 for analogs 31 and 32 refer to the racemic compounds. Enantiomers of 32 were recently separated using chiral AD [amylosetris(3,5-dimethylphenylcarbamate] columns (Thakur etal. 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.

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