Classical/non-classical cannabinoid hybrids; Stereochemical requirements for the southern hydroxyalkyl chain

We have synthesized a range of hybrid classical/ non-classical cannabinoids (CC/NCCs) combining the hexahydrocannabinol dibenzopyran structure with the hydroxyalkyl chain found in CP-55940, in order to investigate the role of the hydroxyalkyl pharmacophore in cannabimimetic activity. This was achieved by synthesizing CC analogs in which the 6 α- and 6β-methyl groups were modified to the corresponding hydroxyethyl groups. Our binding data indicated that β position was the preferred orientation for the hydroxyalkyl moiety, affinity for the CB1 receptor being 20-fold greater for the 6β-hydroxyethyl than the corresponding 6α-analog. Further studies using 6β-hydroxyalkyldibenzopyran analogs varying the southern aliphatic chain length from 6β-hydroxymethyl to 6β-hydroxyethyl to 6β-hydroxypropyl demonstrated little potency change with chain length. Therefore, we concluded that whilst the hydroxyalkyl pharmacophore was strongly affected by its configuration relative to the dibenzopyran ring, the chain length of the hydroxyalkyl moiety (up to the n=3 homolog) was not critical.