A rational search for the separation of psychoactivity and analgesia in cannabinoids.
The compound 9-beta-hydroxy-hexahydrocannabinol [(-)-9 beta-OH-HHC] was designed to fit a combined theoretical profile of an analgesic cannabinoid (equatorial alcohol at C-9, phenol at C-1 and a C-3 side chain) with reduced psychoactivity (axial C-9 substituent which protrudes into the alpha face). (-)-9 beta-OH-HHC was synthesized by the addition of methyl Grignard to 9-oxo-11-nor-HHC. Its alpha epimer was obtained by the regiospecific epoxide ring opening of 9 alpha, 10 alpha-epoxy-HHC acetate. (-)-9 beta-OH-HHC and (-)-9 alpha-OH-HHC were each evaluated in a battery of tests in mice and were found to be 10-25 times less potent than (-)-trans-delta 9-tetrahydrocannabinol (delta 9-THC) in all tests including the tail flick test for antinociception (analgesia). Molecular mechanics calculations [MMP2(85)] revealed that, in the global minimum energy conformation of (-)-9 beta-OH-HHC, the axial methyl at C-9 protrudes into the alpha face of the molecule, while the axial hydroxyl at C-9 in (-)-9 alpha-OH-HHC protrudes into this same face. These calculations also identified a higher energy carbocyclic ring (twist) conformer of each in which there is no protrusion of a C-9 substituent of the carbocyclic ring into the alpha face. The minimal activity of both compounds is attributed to these higher energy forms.(ABSTRACT TRUNCATED AT 250 WORDS)
Reggio
P H
PH
Department of Chemistry, Kennesaw State College, Marietta, GA 30061.
McGaughey
G B
GB
Odear
D F
DF
Seltzman
H H
HH
Compton
D R
DR
Martin
B R
BR
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002187:Cannabinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D002187:Cannabinol; D011619:Psychotropic Drugs; C074005:hexahydrocannabinol