Cannabinol derivatives

Cannabis resin, obtained from the flowering tops of hemp plants, contains a number of dibenzopyrans. The main active constituent is (-)-A1-3,4-numbering system is used). Cannabinol derivatives have slight pharmaceutical potential, e.g. as antiemetics and analgesics, but because of their hallucinatory effects and habituation tendency, which have led to their widespread abuse, they are not prescribed. 

Rhee M-H, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R (1997) Cannabinol derivatives binding to cannabinoid receptors and inhibition of adenylyl cyclase. J Med Chem 40 3228-3233... 

A few studies have been conducted on cannabis and its derivatives. Alozie et al. (3) measured the radioactivity accumulated in various brain areas following the intravenous injection of 3H-THC, 3H-cannabinol, and 3H-cannabidiol to adult male rats. Five minutes after injection, these three labeled compounds exhibited a homogeneous distribution in brain, suggesting that no specific binding occurred. Such studies must be completed by examining the time course of the evolution of 3H-cannabis derivatives in various brain areas before any firm conclusion can be drawn. 

Until the mid 1960 s the only plant cannabinoid whose structure was fully elucidated was cannabinol (CBN) — a constituent which actually may represent an oxidation artifact. However, on the basis of CBN, the main cannabinoid structure skeleton became known. Thus, cannabidiol (CBD), which had been independently isolated in pure form by Adams and by Todd, was correctly assumed to be, like CBN, a terpenoid derivative attached to olivetol. But its exact structure was not elucidated. The psychoactive components of cannabis were assumed to be related tricyclic derivatives. On the basis of the tentatively elucidated constituents, Todd suggested that the cannabinoids may be formed initially in the plant by condensation of a menthatriene with olivetol. 

A -3,4-cis-THC has now been found in Cannabis sativa (Phenotype III) other papers reporting the characterization of compounds from Cannabis sativa concern conclusive identification and synthesis of cannabinodiol, " which is known to result from the photochemical irradiation of cannabinol (Vol. 7, p. 51), and the identification of A -tetrahydrocannabinolic acid " and (+)-cannabitriol (263) " (263) and the corresponding C-2 ethyl ether may be epoxide-derived. " ... 

The simple pyrans are rather unstable compounds and of little biological or industrial significance but some of their benzo derivatives are of considerable interest. Many 2H-1-benzopyrans (chromenes) are found in plants, for example evodionol (126), lapachenole (127), lonchocarpin (128), rottlerine (129) and edulan (130). A few of the constituents of marijuana (hashish) belong to this class, for example cannabinol (131). 

Irradiation of several members of the cannabinoid family has provided useful routes to some derivatives. Cannabichromene (576) is converted into cannabicyclol (577) when it is irradiated in r-butyl alcohol-acetone <71JCS(C)796) and tetrahydrocannabinolic acid (578) is aromatized to cannabinolic acid (579) (70CPB1327). 

Derivative or preparation from Cannabis sativa. This contains several dozen that are chemically related to cannabinol. 

The phenolic hydroxy-group in THC s is important to their pharmacological activity,357 and analgesic properties may be due to metabolism to 7-hydroxy-derivatives (using normal monoterpenoid numbering).358 l-Nor-lj8-hydroxyhexahydrocannabinol is a potent analgesic.359 Cannabinol is a rapidly formed metabolite of A -THC and A6-THC in rats.360 The activity of A6-THC- and cannabidiol-containing polymers is reported.361... 

The tetrahydro cannabinols form acyl derivatives, such as the monoacetates, and ether-derivatives such as the monomethyl ether, with specific rotations corresponding to the rotation of the tetrahydro cannabinol from which each may be formed. 

The classical group consists of dibenzopyran derivatives that are either cannabis-derived compounds (phytocannabinoids) or their synthetic analogues. Notable examples are the phytocannabinoids zl -THC,2l -THC and cannabinol (Fig. 1), and thesynthetic cannabinoids, 11-hydroxy-zl -THC-dimethylheptyl (HU-210), JWH-133, L-759633, L-759656, L-nantradol and desacetyl-L-nantradol (Figs. 4 and 5). 

Hydroxylation at C-7, which is a major metabolic path, leads to the very potent compounds (15) and (16) [85, 86]. The activity of compounds which have very low cannabimimetic activity (for example, cannabinol) may be significantly increased by the introduction of a 7-OH group (75). Monohydroxylation on other positions of the terpene ring also usually leads to active derivatives [87, 88]. Dihydroxylation generally causes loss of activity. 

The site-selectivity of oxidations by mCPBA is demonstrated in the conversion of (4 R = Me or Ph) into the corresponding ene epoxide (5). The product is sensitive to acid, so that the conversion is accomplished in a basic two-phase medium. Normal epoxidation of (6) with mCPBA leads to (7), The stereochemistries for such reactions are shown in the predominant formation of the 3-epoxide (8) (81%) from the parent alkene, with 12% of the a-product. Similar epoxidation of the cannabinol (9) leads to a less stereo-specific isomer distribution of 27.3% and 18.2%. Remarkable stereoselectivity has been shown in the epoxidation of the 14,15-unsaturated oestratrienes (10). Whereas oxidation of 17j3-esters and 17/3-ethers gave 14a,15a-epoxides (< 59%), the 17j3-urethane derivatives displayed a s /w-directive effect to yield 14/3,15j3-epoxides (< 87%). 

The cannabinoids are benzopyran derivatives. Only A9,10"tetrahydro cannabinol (THC) shows hallucinogenic activity. The type and quantity of the constituents depend on the geographical origin of the drug, climatic conditions of growth, time of harvesting and storage conditions. 

CannaMnoids. General term for compounds from Cannabis species and synthetic derivatives of the compounds. Characteristic for the C., apart from their psychotropic activity, is a series of other pharmacological actions. As narcotic drugs are used the female flowering tips ( marihuana) of the Indian hemp (Cannabis sativa) or the resin obtained therefrom ( hashish). Among others, the resin contains dibenzopyran derivatives. Main constituents are cannabidiol, antiepileptic and hypnotic effects, cannabinol and tetrahydro-cannabinols (THC) of the two isomers 4 -THC (known previously as A -THC) and A -THC (with 8,9-double... 

The careful use of mixtures of closely related silyl derivatives can assist in resolving problems arising in GC—MS analyses where spectra lack diagnostic fragmentations or where co-elutions mask compounds of interest [387]. For example, the number of trimethylsilyl groups in the TMS derivative of butyl-A -tetrahydro-cannabinolic add was determined by comparison of the mass spectra of the TMS and TMS-d9 derivatives [387). As part of the same investigation, an interfering peak... 

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