Synthesis and pharmacological activity of some 9-substituted delta 8-tetrahydrocannabinol analogues

Several 9-substituted delta 8-tetrahydrocannabinol (delta 8-THC) analogues were synthesized and evaluated for biological activity in mice. Compounds with phenyl (2b) and butyl (2c) substituents were prepared by the addition of phenyllithium and n-butyllithium, respectively, to (-)-9-nor-9-oxohexahydrocannabinol (1), followed by dehydration, whereas, isopropyl (2d), PhCH2 (2e), and Ph(CH2)2 (2f) derivatives were synthesized via the Grignard reaction with subsequent dehydration. Compounds with C2H5CH(OH) (2g) and CH3CH(OH) (2h) substituents at C-9 were prepared from (-)-9-nor-9-formyl-delta 8-tetrahydrocannabinol acetate (3) by the reaction of ethyl and methyl Grignard reagents, respectively. Biological activity indicated that a methyl group at the C-9 position is, thus far, optimum for producing hypoactivity and hypothermia in mice. In addition, hydroxyethyl substitution at position 9 reduced and antinociceptive activity of delta 8-THC, in contrast to the increased activity reported for hydroxymethyl substitution.