CLASSICAL NONCLASSICAL HYBRID CANNABINOIDS - SOUTHERN ALIPHATIC CHAIN-FUNCTIONALIZED C-6-BETA METHYL, ETHYL, AND PROPYL ANALOGS/

The stereoelectronic requirements for interaction of the southern alip hatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 r eceptors are explored. The stereoselective syntheses of three series o f classical/nonclassical hybrid cannabinoids are described. These comp ounds were designed to investigate the importance of the southern alip hatic hydroxyl (SAH) pharmacophore for cannabimimetic activity. Variat ion in the chain length of the SAH moiety in these 6 beta-(hydroxyalky l)dihydrobenzopyran analogues, from 6 beta-hydroxymethyl to 6 beta-(om ega-hydroxyethyl) and 6 beta-(omega-hydroxypropyl), and the effects of replacing the hydroxyl functionality by hydride and iodide are report ed. Our results indicate that the SAH pharmacophore has less pronounce d effects than the C-3 aliphatic chain on cannabinoid activity. Furthe rmore, it appears that this southern molecular component is capable of interacting with two different subsites on the receptor and that the nature of this interaction is determined by the terminal substituent o n the C-6 beta alkyl group. One of the subsites can accommodate the re latively polar SAH pharmacophore, while the second subsite interacts w ith more hydrophobic C-6 beta substituents and can accommodate large s pherical pharmacophores separated by three methylene carbons from the tricyclic cannabinoid template.