Characterization of the lipophilicity of natural and synthetic analogs of delta 9-tetrahydrocannabinol and its relationship to pharmacological potency.
delta 9-Tetrahydrocannabinol, the primary psychoactive constituent in marihuana, has been studied extensively for the last 20 years; however, the mechanisms responsible for cannabinoid activity in the central nervous system are not well understood. Although it is thought that lipophilicity plays an important role in the actions of cannabinoids, studies have not been conducted to determine whether a relationship exists between the lipophilicity and behavioral potency of cannabinoid analogs. Two procedures were used to obtain n-octanol/water partition coefficients (Po/w) of naturally occurring and synthetic cannabinoids: reverse-phase high-pressure liquid chromatographic estimation of Po/w and computer calculation of Po/w based on molecular structure. The Po/w value for delta 9-tetrahydrocannabinol obtained in this study, 9.44 x 10(6), is much greater than previously reported values obtained using shake-flask methodology, yet it is in agreement with the computer calculation based on molecular structure or molecular volume. The lipophilicity of the analogs determined in this study ranged from Po/w values of 3.92 x 10(2) to 1.93 x 10(11). All pharmacologically active cannabinoid compounds were extremely lipophilic (log Po/w values greater than 4.5). Several structural alterations were found to exert considerable influence on the lipophilicity of cannabinoid analogs. Increasing the length of the side chain in a homologous series of analogs results in an increase in lipophilicity of approximately 3-fold for each CH2 group added. Introduction of a single hydroxyl group decreased lipophilicity 3- to 40-fold, depending on the site of attachment. The behavioral potency of active analogs was not found to be correlated to lipophilicity. Therefore, data obtained in this study suggest that lipophilicity is a component, but not a primary determinant of pharmacological activity in the cannabinoids.
Thomas
B F
BF
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond.
Compton
D R
DR
Martin
B R
BR
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003201:Computers; D013759:Dronabinol / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D012995:Solubility; D013329:Structure-Activity Relationship
D013759:Dronabinol