Cannabinoids described

Lichtman et al. 2001 Tzavaraet al. 2000). A dog model of precipitated cannabinoid withdrawal, which includes increased salivation, vomiting, diarrhea, restless behavior, and trembling, has also been described (Lichtman et al. 1998). 

Seventy cannabinoids from C. sativa have been described up to 2005 [2j. Mostly they appear in low quantities, but some of them shall be mentioned in the following overview - especially because of their fimctions in the biosynthesis of A9-THC and their use in medicinal applications. 

The lUPAC name of cannabidiol is 2-[(lS, 6iI)-3-methyl-6-prop-l-en-2-yl-l-cyclohex-2-enyl]-5-pentyl-benzene-1,3-diol. Cannabidiol (CBD, 2.9) in its acidic form cannabidiolic acid (CBDA, 2.10) is the second major cannabinoid in C. sativa besides A9-THC. As already mentioned for A9-THC, variations in the length of the side chain are also possible for CBD. Important in this context are the propyl side chain-substituted CBD, named cannabidivarin (CBDV, 2.11), and CBD-C4 (2.12), the homologous compound with a butyl side chain. Related to the synthesis starting from CBD to A9-THC as described in Sect. 3.1, it was accepted that CBDA serves as a precursor for THCA in the biosynthesis. Recent publications indicate that CBDA and THCA are formed from the same precursor, cannabigerolic acid (CBGA), and that it is unlikely that the biosynthesis of THCA from CBDA takes place in C. sativa. 

The late cannabinoid pathway starts with the alkylation of ohvetolic acid (3.2 in Fig. 4) as polyketide by geranyl diphosphate (3.1) as the terpenoid unit. Terpenoids can be found in all organisms, and in plants two terpenoid pathways are known, the so called mevalonate (MEV) and non-mevalonate (DXP) pathway as described by Eisenrich, lichtenthaler and Rohdich [23,24,29,30]. The mevalonate pathway is located in the cytoplasm of the plant cells [30], whereas the DXP pathway as major pathway is located in the plastids of the plant cells [29] and delivers geranyl diphosphate as one important precursor in the biosynthesis. 

Whilst for the analysis of plant material for cannabinoids both GC and HPLC are commonly used, in analytical procedures the employment of GC-based methods prevails for human forensic samples. Nonetheless, the usage of HPLC becomes more and more of interest in this field especially in combination with MS [115-120]. Besides the usage of deuterated samples as internal standards Fisher et al. [121] describe the use of a dibrominated THC-COOH (see 7.5). The usage of Thermospray-MS and electrochemical detection provide good performance and can replace the still-used conventional UV detector. Another advantage in the employment of HPLC rather than GC could be the integration of SPE cartridges, which are needed for sample preparation in the HPLC-system. 

Before the discovery of specific cannabinoid receptors, the term cannabinoid was used to describe the biologically active constituents of the Cannabis sativa plant, including A -THC (67), cannabidiol (68) and their analogues and derivatives, many of which have characteristic pharmacological effects. 

A -THC, the main psychoactive component of cannabis, is a moderately potent partial agonist of the CBi and CB2 receptors, while cannabidiol has little affinity for either receptor (Table 6.7). The term classical cannabinoids is used to describe cannabinoid receptor modulators structurally related to (67), which have a tricyclic dibenzopyran core. While several other structural types of cannabinoid receptor modulators have been discovered in recent years, the classical cannabinoids are still by far the most extensively studied group in terms of SAR and pharmacology. 

The term non-classical cannabinoids is applied to a group of bicyclic compounds identified by researchers at Pfizer in the 1980s [129], These compounds lack the pyran ring of the classical cannabinoids and the second phenolic hydroxyl group of the cannabidiols, resulting in a simplified substructure represented by CP 47,497 (192) [130, 131], The non-classical cannabinoids still retain the three main pharmacophoric elements described above for the classical cannabinoids and the SAR in these regions parallels that of the classical cannabinoids [132]. 

Classical/non-classical hybrid cannabinoids, such as (197) and (198), have been described by Tins et al. [137, 140]. In these compounds, a southern... 

In addition, Novartis filed a patent application on a series of quinazolines as cannabinoid agonists [209]. Compound (320) is one of the two compounds specifically claimed and exhibited CBi and CB2 binding with if values of 34 and 11 nM, respectively. It was shown to be a full agonist at the CBi receptor with an EC50 of 132nM (no functional data for the CB2 receptor). Compound (320) was also active in the neuropathic pain model described above with an ED50 of 0.5mg/kg after oral dosing. 

Martin and co-workers [196] have also published on the discovery and SAR of pyrazole cannabinoids as described in the CBi agonist section. The analogues were tested for CBi receptor binding affinity and in a battery of in... 

Several tentative cannabinoid receptors have been proposed. The best one described is a receptor partly identified by Wagner etal. It mediates a mesenteric vasodilator response to anandamide and R-methanandamide and is distinct from the CBi receptor. 

Later, we described the isolation of a second type of cannabinoid receptor ligand, 2-arachidonoyl glycerol (2-AG) (K = 5-85 0.12 xM), an ester isolated from canine gut. " This was the first putative endogenous cannabinoid receptor ligand isolated from a peripheral tissue. Later, Sugiura et al isolated independently this compound from brain. 

Forensic analysis of street drugs include that of cocaine together with excipients frequently encountered (579), amphetamines 080), and dyes found in heroin samples 081). An on-line photochemical derivitization of cannabinoids has been described 082). Other pharmaceutical agents studied in formation include nortriptyline in tablets. 083), glycyrrhizic acid from licorice extract 084, 585), pirimiphos methyl 086), digitalis glycosides 0S7), pilocarpine 088), and its antagonist atropine 009). 

Further syntheses of [4",5"- H2]- and [4",5"- H2]-A -THC and -A -THC have been described (c/. Vol. 7, p. 50), and Crombie et al. have extended miniaturized synthesis and chromatographic analysis (c/. Vol. 6, p. 49) to cannabinoid esters,large-scale syntheses of which using acid-catalysed terpenylation of methyl olivetolate have also been described ester cleavage, using lithium n-... 

Little is known about the pharmacology of DMHP and DMHP acetate, but the reference compound, THC, has been extensively described both in humans and in animals. Many reviews and symposia have discussed marijuana and the cannabinoids.6>10>l9 26,39 National Insti-... 

In 1980 the total number of natural compounds identified in C. sativa L. was 423.3 By 1995 the number had risen to 483, and recently 6 new compounds, 4 new cannabinoids and 2 new flavonoids, have been described.4... 

Lactone 5 can be obtained in both enantiomeric forms or as a racemate according to the described procedure. The reaction sequence includes the in situ formation of an alkylidene-1,3-dicarbonyl system 7 which can act as a heterodiene in an intramolecular hetero-Diels-Alder addition. A small amount of the ene product 4 with de > 98% is formed at room temperature as well. The remarkable selectivity in formation of diastereomer 3 is explained by an energetically more favorable exo transition state 8 with a pseudo-chair arrangement having the methyl group quasi-equatorial. Polycyclic cis-fused compounds can also be synthesized by the procedure above,9 and a related sequence to the cannabinoid skeleton has been described using appropriate 1,3-dicarbonyl reactants.10... 

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