Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte antiadhesion activities.
Two strategies for the design of therapeutically useful cannabinoids have been combined to produce compounds with greatly increased antiinflammatory activity and with a low potential for adverse side effects. Enantiomeric cannabinoids with a carboxylic acid group at position 7 and with an elongated and branched alkyl sidechain at position 5' have been synthesized and tested for antiinflammatory activity. They were effective when given orally at doses of 10 micrograms/kg in reducing paw edema in mice that had been induced by either arachidonic acid or platelet activating factor. Leukocyte adhesion to culture dishes was also reduced in peritoneal cells from mice in which the cannabinoids were orally administered in the same dose range as for the paw edema tests. Antinociception could be observed in the mouse hot plate assay; however, little stereochemical preference was seen in contrast to the above tests where the 3R,4R compounds are more active than the 3S,4S enantiomers. Finally, in agreement with earlier reports on the naturally occurring pentyl side chain acids, the synthetic acids showed little activity in producing catalepsy in the mouse, suggesting that they would be nonpsychotropic in humans.
Burstein
S H
SH
Department of Biochemistry & Molecular Biology, University of Massachusetts Medical School, Worcester 01655.
Audette
C A
CA
Breuer
A
A
Devane
W A
WA
Colodner
S
S
Doyle
S A
SA
Mechoulam
R
R
D000698:Analgesia; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016718:Arachidonic Acid; D002186:Cannabinoids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002375:Catalepsy / Q000139:chemically induced; D002448:Cell Adhesion / Q000187:drug effects*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D010147:Pain Measurement; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002186:Cannabinoids; D016718:Arachidonic Acid