9-Tetrahydrocannabinol 11-hydroxy

THC undergoes metabolic degradation in the liver, where it is hydroxylated to 11-hydroxy tetrahydrocannabinol (THC-llOH). The latter, still with psychoactive activity, is oxidized to A9-THC-COOH, an inactive metabolite which is conjugated as 1 l-nor-A9-tetrahydrocannabinol-9-carboxy-glucuronide (A9-THC-COOH-glu), more hydrophilic metabolite and therefore easily excreted in the urine [32],... 

There are over 400 constituent compounds in marijuana. More than 60 of these are pharmacologically active cannabinoids, of which 4 are the most important. The most psychoactive is delta-9-tetrahydrocannabinol (A-9-THC). The other three important natural cannabinoids are A-8-THC, cannabinol and cannabidiol (Kumar et al., 2001). In addition, some of the metabolites of THC, such as 11-hydroxy-A-9-THC, are also psychoactive. As a consequence and contrary to many other drugs, the metabolism of THC in the liver does not decrease intoxication, rather it prolongs it. 

As it can be observed in Fig. 2, three out of the 16 investigated compounds, namely, heroin, lysergic acid diethylamide (LSD), and its metabolite 2-oxo, 3-hydroxy-LSD (O-H-LSD), were not detected in any wastewater sample. Two other target analytes, 6-acetyl morphine (6ACM) and A9-tetrahydrocannabinol (THC), were only present in influent wastewaters and with low detection frequencies. The most ubiquitous compounds, present in all influent and effluent wastewater samples analyzed, were the cocaine metabolite benzoylecgonine, and the amphetamine-like compounds ephedrine (EPH) and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). Cocaine, cocaethylene (CE, transesterification product of cocaine formed after the joint consumption of cocaine and ethanol), and morphine (MOR) were detected in all influent, but not in all effluent wastewaters (see Fig. 2). 

There are approximately 400 chemicals in the cannabis plant, 61 of which are unique and may be called cannabinoids. The most common psychoactive cannabinoid is A9-tetrahydrocannabinol (A9-THC) (Robbers et al. 1996) (figure 10.4). Other psychoactive cannabinoids include A8-tetrahydrocannabinol (A8-THC), ll-hydroxy-A8-tetrahydrocannabinol (11-OH-A9-THC), and 9-nor-9 j8-hydroxyhexahydrocannabinol p-... 

Maralikova B, Weinmann W. 2004 Simultaneous determination of Delta9-tetrahydrocannabinol, ll-hydroxy-Delta9-tetrahydrocannabinol and ll-nor-9-carboxy-Delta9-tetra-hydrocannnabinol in human plasma by high-performance liquid chromatography/tandem mass spectrometry. J Mass Spectrom 39 526. 

Clinical investigations of A -tetrahydrocannabinol (4,5) and ll-hydroxy-A -tetrahydrocannabinol (6) have relied upon analysis by radioactive labeling. However, the study of distribution, metabolism and excretion of the drug and its metabolites under chronic or "street" conditions demands nonradioactive analytical procedures. When plasma suspensions of l c-A -tetrahydrocan-nabinol were administered intravenously to three dogs at doses of 0.1 - 2.0 mg/kg and plasma levels of 1 were followed for up to 7000 minutes, no significant differences were seen in 1 plasma levels as determined by liquid scintillation and electron capture detection (GLC) after HPLC collection. 

A9 Tetrahydrocannabinol and ll-hydroxy-A -tetra-hydrocannabinol were quantitatively separable on the reverse phase HPLC system at 47% (or less) acetonitrile in water. The collection efficiencies in the chosen ranges were 98% of the recoverable radioactivities of 8H-ll-hydroxy-A8-tetrahydrocannabinol and l c-A8-tetrahydrocannabinol (Fig. 5). A8- and A8-Tetrahydro-... 

An equal amount of A9-tetrahydrocannabinol and 11-hydroxy-A9-tetrahydrocannabinol in 2 ml dog plasma (the pH was adjusted between 9.5 and 11.0 by addition of 0.1 N Na2C03 prepared from water purified using a Bondapak C 18R column) was extracted in a silylated tube by heptane with 1.5% isoamyl alcohol. In this extract, the compounds were separated from a majority of extracted components by reverse phase HPLC. The reduction in potential contaminants from plasma observable on GLC was demonstrated by flame ionization GLC analysis (17,18) both before and after HPLC treatment (Fig. 6). 

The normal phase HPLC (20% chloroform in heptane) could separate A9-tetrahydrocannabinol from monohydrox-ylated metabolites and from 11-hydroxy-A tetrahydrocannabinol. However, a minor overlap could be avoided by collecting the tetrahydrocannabinol 1 in a slightly narrower volume range. The prior heptane extraction of alkalinized plasma had separated these non-polar constituents from any acidic metabolite. This separation of plasma extracts and normal phase HPLC collection of volumes in the appropriate range resulted in a substantial reduction in GLC background from plasma components for derivatized tetrahydrocannabinol analyzed with electron capture (63 1) detection. 

Metabolism of I in humans has been studied by several groups (5-8) with findings that 11-hydroxy A9 -tetrahydrocannabinol (V) and ll-nor-A9-tetrahydrocanni-binol-9-carboxylic acid (VI) are the principal metabolites. ... 

Cannabis is extensively metabolized in the human to 11 hydroxy- and 8 3 hydroxy-A9-tetrahydrocannabinol (11 OH and SP OH-THC) and finally to 11 nor-A9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), which is conjugated with glucuronic acid to a variable extent. 

It is interesting to contemplate the structural similarity predicted for LSD and serotonin and the known CNS activity of the former and to compare this with the CNS activity and structure of the cannibinol metabolite, ll-hydroxy-A9-tetrahydrocannabinol. It is conceivable that similar mechanisms may prevail in the CNS as a result of similar stereochemical presentations of comparable charged atoms to the serotonin receptor. 

Klein TW, Newton CA, Widen R, Friedman H (1985) The effect of del ta- 9- tetrahydrocannabinol and 11 -hydroxy-delta-9- tetrahydrocannabinol on T-lymphocyte and B-lymphocyte mitogen responses. J hnmunopharmac 7 451 66. 

The primary active component of cannabis is A9-tetrahydrocannabinol (THC), which is responsible for the greater part of the pharmacological effects of the cannabis complex. A8-THC is also active. However, the cannabis plant contains more than 400 chemicals, of which some 60 are chemically related to A9-THC, and it is evident that the exact proportions in which these are present can vary considerably, depending on the way in which the material has been harvested and prepared. In man, A9-THC is rapidly converted to 11-hydroxy-A9-THC (3), a metabolite that is active in the central nervous system. A specific receptor for the cannabinols has been identified it is a member of the G-protein-linked family of receptors (4). The cannabinoid receptor is linked to the inhibitory G-protein, which is linked to adenyl cyclase in an inhibitory fashion (5). The cannabinoid receptor is found in highest concentrations in the basal ganglia, the hippocampus, and the cerebellum, with lower concentrations in the cerebral cortex. 

Martin, B.R. Kallman, M.J. Kaempf, G.F. Harris, L.S. Dewey, W.L. and Razdan, R.K. Pharmacological potency of R- and S-3 -hydroxy-delta-9-tetrahydrocannabinol Additional structural requirement for cannabinoid activity. Pharmacol Biochem Behav 21 61-65, 1984. 

Ring condensation may be used to produce the rans-delta-9-tetrahydrocannabinol (A9-THC) from 6,12-dihydro-6-hydroxy-cannabidol. This reaction is performed in a suitable solvent with the use of suitable catalysts and water binding substances. The solvent is in the form of a hydrocarbon, as for instance hexane, heptane, cyclohexane, petroleum ether, aromatic hydrocarbons, such as for instance benzene, toluene, chorinated hydrocarbons, such as for instance methylene chloride, chloroform and dichloroethane. Preferably methylene chloride and chloroform are used. Furthermore mixtures of the solvents may be used. 

Previous work with A6-Tetrahydrocannabinol [(3R,4R) 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-l -ol, hereinafter referred to as A6-THC], has indicated that derivatives of this compound may prove clinically useful. The 7-carboxy derivative of A6-THC [A6-THC-7-oic acid] has been reported to be a non-psychoactive, potent antagonist to endogenous platelet activating factor and, thus, a useful treatment for PAF-induced disorders, such as asthma, systemic anaphylaxis, and septic shock. (U.S. Pat. No. 4,973,603, issued Nov. 27, 1990 to Sumner Burstein). Another derivative, (3S,4S)-7-hydroxy-A6-THC-l,l-dimethylheptyl, has been reported to possess analgesic and antiemetic activities. (U.S. Pat. No. 4,876,276). 

Results from previous experiments, in which we compared the inhibitory effects of the 1,1-dimethylheptyl homologs of (+) and (-)-ll-hydroxy-delta-8-tetrahydrocannabinol on the electrically-evoked twitch response of the mouse vas deferens, indicate that this preparation is suitable as a model for investigating the mode(s) of action of psychotropic cannabinoids. R. G. Pertwee, L. A. Stevenson, D. B. Elrick, R. Mechoulam, A. D. Corbett, Brit. J. Pharmacol. 105, 980 (1992). Anandamide produced a concentration-dependent inhibition of the twitch response (FIG. 2). The inhibition was not reversed by naloxone (300 nM). The levels of inhibition are comparable to those of binding to the receptor. 

Delta-9-THC is metabolized by the liver to ll-hydroxy-delta-9-tetrahydrocannabinol (ll-OH-delta-9-THC) which also has psychoactive effects. This metabolite is then itself broken down into other metabolites, which are in turn broken down further, and eventually these metabolites are eliminated through the feces and the kidney. About 50 percent of the delta-9-THC content in the body is eliminated in the form of metabolites in the first twenty-fom hours. However, traces of the drag can still be found in the human body as long as eight days later. 

Huffman JW, BushellSM, Miller JRA, WUey JL, Martin BR (2002) 1-methoxy-, 1-deoxy-ll-hydroxy- and 11-hydroxy-l-methoxy-zl8-tetrahydrocannabinols new selective ligands for the CB2 receptor. Bioorg Med Chem 10 4119-4129... 

More recently, this group prepared three series of new CBs l-methoxy-3-(l, l -dimclhylalkyl)-A -tetrahydrocannabinol, l-deoxy-ll-hydroxy-3-(l, T-dimethyl-alkyl)-A -tetrahydrocannabinol and 11-hydroxy- l-methoxy-3-(l, f-dimelhyl-alkyl)-A -tetrahydrocannabinol, which contain alkyl chains from dimethylethyl to dimethylheptyl appended to C-3 of the CB. All of these compounds had greater affinity for the CB2 receptor than for the CBi receptor however, only 1-methoxy-... 

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