Tetrahydrocannabinols, preparation

A serious problem in the early Western medicinal use of C. sativa, mainly as a tincture, was its highly variable activity and inconsistent results. Medicinal preparations have to handle several particularities due to the structure of the active ingredients of C. sativa. The identity of the main active constituent of C. sativa, A9-tetrahydrocannabinol (INN dronabinol) remained unknown until 1964 [128] standardized C. sativa preparations were not available. The plant itself is found in several different chemotypes, which added to the unpredictable nature of early medicinal preparations. 

Cannabis preparations are smoked in order to deliver their psychoactive substances, cannabinoids, especially THC delta-9-tetrahydrocannabinol (THC) (Fig. 13—14). 

A9-Tetrahydrocannabinol (A9-THC) is considered to be the predominant compound in preparations of C. sativa (marijuana, hashish, bhang) that is responsible for the central nervous system effects in humans. The recognized central nervous system responses to these preparations include alterations in cognition and memory, euphoria, and sedation. Potential therapeutic applications of cannabis preparations that are of either historical or contemporary interest include analgesia, attenuation of the nausea and vomiting of cancer chemotherapy, appetite stimulation, decreased intestinal motility of diarrhea, decreased bronchial constriction of asthma, decreased intraocular pressure of glaucoma, antirheumatic and antipyretic actions, and treatment of convulsant disorders. These effects have been reviewed recently (Howlett, 1995). 

The main active ingredients of cannabis are cannabinol, cannabidiol and several isomers of tetrahydrocannabinol, of which delta-9-tetrahydro-cannabinol (THC) is probably responsible for most of the psychoactive effects of the various preparations. It is of interest to note that THC does not contain nitrogen in its three-membered ring system. The structure of THC is shown in Figure 15.8. 

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). 

In order to identify cannabis products, one of the most frequently used methods is gas chromatography-mass spectrometry (GC-MS). The identification relies on the presence of A -THC, CBD and CBN in the sample, and to a lesser extent, the presence of A -THC (the isomer of the active principle of cannabis) and A -tetrahydrocannabinolic acid. The following presents a method that has been found to work, although there are a number of similar methods reported in the literature [9], The sample is prepared for GC-MS analysis as follows ... 

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. 

The use of substituted alkoxyacetylenes in synthesis is fairly limited due to the lack of simple, general methods for their preparation. However, silyloxyacetylenes are easier to make and can be prepared from esters in a one-pot operation. In the laboratory of C.J. Kowalski, research has shown that silyloxyacetylenes could be successfully used in the Danheiser benzannuiation. This modification was used in the total synthesis of A-6-tetrahydrocannabinol. 

Delta-9-Tetrahydrocannabinol (Delta-9-THC) and, to a small extent, also Delta-8-THC are the biologically active constituents in extracts of the plant Cannabis sativa (marihuana, hashish) and are responsible for the effects on the human central nervous system (CNS). Potential historical and contemporary therapeutic uses of cannahis preparations include, interalia, analgesia, emesis, anorexia, glaucoma and motor disorders. 

Several investigations have been carried out over the years to isolate THC from the plant material, mostly to determine its chemical structure or to investigate the phytochemistry of the plant. In 1942, Wollner, et al., (11) reported the isolation of tetrahydrocannabinol from cannabis extract red oil . Red oil was prepared by extraction of the plant material with ether, followed by distillation of the concentrated extract at room pressure followed by redistillation under reduced pressure (15-50 mm Hg). 

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. 

Pertwee RG, Fernando SR, Griffin G, Ryan W, Razdan RK, Compton DR, Martin BR (1996b) Agonist-antagonist characterization of 6 -cyanohex-2 -yne-A8-tetrahydrocannabinol in two isolated tissue preparations. Eur J Pharmacol 315 195-201... 

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-... 

In an early study, Turkanis et al. (1991) showed that -tetrahydrocannabinol inhibits voltage-dependent sodium channels the involved primary receptor was not identified in this study. More recently, it was observed that anandamide and the synthetic CB1/CB2 receptor agonist WIN55212-2 inhibited voltage-dependent sodium channels in synaptosomes prepared from mouse brain (Nicholson et al. 2003). Since the effects were not attenuated by fhe CBi receptor antagonist AM251, the involvement of CBi receptors can be excluded. 

Methyl olivetolate (140) and its regioisomer (141) have been prepared in a regiocontrolled manner by the condensation of (63) with the two 1,3-electrophiles (142) and (143) respectively (Scheme 48). - - In these cases, the reactivity order in the electrophilic components is acid chloride > acetal > ester. This reaction has been used in a biomimetic synthesis of (-)-A -tetrahydrocannabinol (144). 

Mechoulam, Chemistry and Biochemistry of Cannabis," 76 75 L.E. Hollister, Tetrahydrocannabinol Isomers and Homologues Contrasted Effects of Smoking, Nature 111 (1970) 968 G.W. Kinzer et al., The Fate of the Cannabinoid Components of Marijuana During Smoking, Bulletin on Narcotics 26 (1974) 41 A.R. Patel and G.B. Gori, Preparation and Monitoring of Marijuana Smoke Condensate Samples, Bulletin on Narcotics 27 (1975) 47. 

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