CLASSICAL NONCLASSICAL CANNABINOID HYBRIDS - STEREOCHEMICAL REQUIREMENTS FOR THE SOUTHERN HYDROXYALKYL CHAIN

We have synthesized a range of hybrid classical/ non-classical cannabi noids (CC/NCCs) combining the hexahydrocannabinol dibenzopyran structu re with the hydroxyalkyl chain found in CP-55940, in order to investig ate the role of the hydroxyalkyl pharmacophore in cannabimimetic activ ity. This was achieved by synthesizing CC analogs in which the 6 alpha - and 6 beta-methyl groups were modified to the corresponding hydroxye thyl groups. Our binding data indicated that beta position was the pre ferred orientation for the hydroxyalkyl moiety, affinity for the CB1 r eceptor being 20-fold greater for the 6 beta-hydroxyethyl than the cor responding 6 alpha-analog. Further studies using 6 beta-hydroxyalkyldi benzopyran analogs varying the southern aliphatic chain length from 6 beta-hydroxymethyl to 6 beta-hydroxyethyl to 6 beta-hydroxypropyl demo nstrated little potency change with chain length. Therefore, we conclu ded that whilst the hydroxyalkyl pharmacophore was strongly affected b y its configuration relative to the dibenzopyran ring, the chain lengt h of the hydroxyalkyl moiety (up to the n=3 homolog) was not critical.