Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs.
Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (-)-11-OH-delta 8-THC-dimethylheptyl was 80-1150 times more potent than delta 9-THC. Stereospecificity was demonstrated by its (+)-enantiomer which was more than 1400-7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (-)-11-OH-delta 9-THC-DMH was found to be equipotent with (-)-11-OH-delta 8-THC-DMH. The aldehyde (-)-11-oxo-delta 9-THC-DMH was 15-50 times more potent than delta 9-THC. Surprisingly, (-)-11-carboxy-delta 9-THC-DMH was also active, being slightly more potent than delta 9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to delta 9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.
Martin
B R
BR
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond 23298.
Compton
D R
DR
Thomas
B F
BF
Prescott
W R
WR
Little
P J
PJ
Razdan
R K
RK
Johnson
M R
MR
Melvin
L S
LS
Mechoulam
R
R
Ward
S J
SJ
D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003511:Cyclohexanols / Q000378:metabolism / Q000494:pharmacology; D013759:Dronabinol / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D008968:Molecular Conformation; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol