Hashish: Synthesis and central nervous system activity of some novel analogues of cannabidiol and oxepin derivatives of Delta super(9)-tetrahydrocannabinol

Several C-10 substituted cannabidiol (CBD) derivatives and novel oxepin derivatives of Delta super(9)-tetrahydrocannabinol ( Delta super(9)-THC) were synthesized and evaluated for biological activity in mice and dogs. Incorporation of N-ethyl (10), N-methyl-N-propargyl, and morpholino groups in CBD at position 10 resulted in analogues that were more potent than CBD in producing hypoactivity in mice. These anlogues had relatively little effect on rectal temperature. Selected substitutions at C-10 also resulted in analogues that were partially effective in blocking Delta super(9)-THC antinociceptive activity. This blockade was observed particularly in compound 10, which also showed unusually toxic properties. Incorporation of a seven-membered oxepin in the Delta super(9)-THC structure eliminated cannabinoid activity although substitution of the pentyl side chain with a 1,2-dimethylheptyl in the oxepin 14b resulted in CNS depression in mice.