Cannabinoids structure

Most of the tests that were developed for detection of cannabinoids in plants have shown that antibodies are specific for the cannabinoid structure. Because of this specifity these tests can be extensively applied for the detection of cannabinoids and metabolites in human body fluids such as plasma, urine, and oral fluids. Many different kits based on these methods were developed and they are commercially available, for example Oratect, Branan or Uplink, and OraSure. We must consider, however, that no humans have the same metabolite profile in their blood and that cross-reactivity may always occur [122,123]. Nevertheless, these tests offer a simple way of excluding most of the suspicious samples, but the results still have to be confirmed with a second method such as GC-MS [124,125]. 

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. 

The psychoactive and medicinal chemical compounds found in the resin of the marijuana plant are known as cannabinoids. The cannabis plant contains more than 460 known compounds over 60 of these have a cannabinoid structure. The only cannabinoid that is highly psychoactive and present in large amounts in the resin of the cannabis plant is tetrahydrocannabinol, or THC. The other two major cannabinoids are the cannabidiols and the cannabinols. It appears that the cannabis plant first produces the mildly active cannabidiols, which are converted to the more psychoactive THCs and then broken down to relatively inactive... 

Bisogno T (2008) Endogenous cannabinoids structure and metabohsm. J Neuroendociinol 20 1-9 Bisogno T, Melck D, Bobrov MY, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V (2000) N-acyl-dopamines novel synthetic CBl cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimemetic activity in vitro and in vivo. Biochem J 351 817-824... 

Loev, B. Bender, P.E. Dowalo, F. Macko, E. and Fowler, P.J. Cannabinoids. Structure activity studies related to 1,2-dimethyl heptyl derivatives. J Med Chem 16 1200-1206,1973. 

Srebnik, M. Lander, N. Brener, A. and Mechoulam, R. Base catalysed double bond isomerizations of cannabinoids Structural and stereochemical aspects. J Chem Soc Perkin Trans 12881-2886,1984. 

Loev, B. et al. Cannabinoids Structure-Activity Studies Related to 1, 2-Dimethylhemtyl Derivatives. Journal of Medicinal Chemistry 16... 

Cannabinoid structure-activity requirements (SAR) literature has primarily focused on CBj-receptor affinities of fatty acid ethanolamides, such as AEA and its analogs. Recently, however, Sugiura has begun to develop an SAR for 2-AG and its analogs based on a functional assay of Ca + mobilization (Sugiura et al., 1999 Sugiura and Waku, 2000). Because of their difference in basis, each of these SARs will be presented separately here. 

Compton DR, Rice KC, De Costa BR, Razdan RK, Melvin LS, Johnson MR, and Martin BR (1993) Cannabinoid structure-activity relationships correlation of receptor binding and in vivo activities. J Pharmacol Exp... 

By definition, cannabinoids comprise a variety of distinct chemical classes which bind to the cannabinoid receptor. These include the classical cannabinoids structurally related to tetrahydrocannabinol, the non-classical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and atylsulphonamides and additional compounds that do not fall into these standard classes. According to their production and origin, there are three types of cannabinoids phytocannabinoids, endogenous cannabinoids, and synthetic cannabinoids. 

Gaoni Y, Mechoulam R Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86 1646—1647, 1964 Gardner EL Addictive potential of cannabinoids the underlying neurobiology. Chem Phys Lipids 121 267-290, 2002... 

Matsuda LA, Lolait SJ, Brownstein MJ, et al Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 364 561—564, 1990... 

After identification of A9-THC as the major active compound in Cannabis and its structural elucidation by Mechoulam and Gaoni in 1964 [66], a lot of work was invested in chemical synthesis of this substance. Analogous to the biosynthesis of cannabinoids, the central step in most of the A9-THC syntheses routes is the reaction of a terpene with a resorcin derivate (e.g., olivetol). Many different compounds were employed as terpenoid compounds, for example citral [67], verbenol [68], or chrysanthenol [69]. The employment of optically pure precursors is inevitable to get the desired (-)-trans-A9-THC. 

Most relevant for the affinity for A9-THC and analogs to CB-receptors are the phenolic hydroxyl group at C-1, the kind of substitution at C-9, and the properties of the side chain at C-3. Relating to the structure-activity relationships (SAR) between cannabinoids and the CB-receptors, many different modified strucfures of fhis subsfance group were developed and fesfed. The most important variations include variations of the side chain at the olivetolic moiety of the molecules and different substitutions at positions C-11 and C-9. One of the most popular analogous compounds of A9-THC is HU-210 or (-)-trans-ll-OH-A8-THC-DMH, a cannabinoid with a F,l-dimethylheptyl side... 

In the search for new anti-inflammatory drugs structurally derived from indomethacine [147], Pravadoline showed psychotropic side effects in clinical trials. It became apparent that these effects are mediated through the cannabinoid receptor. Optimization of the structure Anally led to WIN-55,212-2 (8.6), which has a higher affinity to the CBl receptor than THC [148]... 

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. 

During the 1940s, more than 15 years before the structure of (67) was elucidated as the major psychoactive constituent of marijuana [90] and 40 years before the identification of specific cannabinoid receptors, Adams and co-workers [91, 92] demonstrated that a T,2 -dimethylheptyl (T,2 -DMH) side chain was the optimal 3-alkyl substituent for carmabinoid activity in vivo in the A ° -THC series. In this early research, the ataxia test in dogs was used as a standard measure of psychoactive cannabinoid activity. The isomeric l, l -DMH side chain was found to be less potent than the l, 2 -DMH one in the series, but the two side chains have similar... 

All the aforementioned protein members of the cannabinoid system are large, membrane-bound proteins therefore, it is particularly difficult to obtain direct information about their tertiary structure. Thus, at the present time, structure-based drug design is not feasible. Detailed exploration of the SAR and subsequent ligand-based design are the most appropriate means for the development of molecular probes for these proteins. 

Many classical cannabinoid analogs have been synthesized and evaluated pharmacologically and biochemically (Razdan, 1986 Mechou-lam, 1999). The CC structural features that seem to be important for cannabimimetic activity (Makriyannis, 1990) are as follows ... 

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