A cannabinoid derived prototypical analgesic.
The synthesis and analgesic testing of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (1) are described. Prior (SAR) studies led us to conclude that the pyran ring of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC) was not necessary for the expression of biological activity in this series of cannabinoids. Analysis of models and the use of molecular mechanics calculations suggested that a simpler compound, such as 1, would possess the biological activity of HHC. Compound 1 was prepared in nine steps from [3-(benzyloxy)phenyl]acetonitrile (2). Biological testing in five models of pain shows that compound 1 and morphine are equally potent as analgesics and demonstrates that the pyran ring of HHC is not necessary for biological activity. Further simplification of 1 was pursued by the synthesis of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol (17), but this derivative exhibits significantly reduced analgesic activity.
D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D002186:Cannabinoids / Q000138:chemical synthesis*; D003511:Cyclohexanols / Q000138:chemical synthesis* / Q000627:therapeutic use; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D010146:Pain / Q000503:physiopathology; D051381:Rats; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D000700:Analgesics; D002186:Cannabinoids; D003511:Cyclohexanols; D007202:Indicators and Reagents; C036088:CP 47497