Cannabinoids values

Fig. 1 Concentrations reported for opiods and cannabinoids in surface water of different European countries. MOR morphine Nor-MOR nor-morphine 6ACM 6-monoacetyl morphine HER heroin MET methadone EDDP 2-ethylidene-l,5-dimethyl-3,3 diphenylpyrrolidine THC A9-tetrahydro-cannabinol THC-COOH 11-nor 9-carboxy-THC N/A Values not availabe, not measured...

Sanofi-Aventis has disclosed a series of piperidine- and piperazine-alkyl carbamates as cannabinoid and/or FAAH modulators. No compounds are specifically claimed in the patent. Compound (60) is reported to have an IC50 value of 85 and is active in a mouse pain model [75]. 

A number of protocols are available for measuring cannabinoid-binding affinity and as such there is a variation in reported K[ values for end-ocannabinoids across labs. For this reason, wherever possible, the relative affinity compared to AEA (measured in that protocol) will be given in an attempt to provide a benchmark for comparison. 

Novartis AG has filed a patent application on novel naphthalene derivatives as potent cannabinoid agonists, especially at the CBi receptor [208]. One compound was specifically claimed, the naphthalene derivative (319), which exhibited CBi binding with a if value of 15 nM. This compound was also active in an in vivo model of neuropathic pain, reversing hyperalgesia... 

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. 

Method. The derivatives are formed by shaking the sample (dissolved in acetone) for 1 h at 45 °C with a 3-5 molar excess of recrystallized DNS-C1. The reaction is buffered at pH 10.8.0.25 ml of 1N sodium hydroxide is then added in order to hydrolyze the unchanged DNS-C1. The derivatives are extracted with 3 ml of ethyl acetate after addition of 1 ml of a saturated aqueous solution of sodium chloride to the reaction mixture. The organic phase is used for TLC on activated layers of silica gel G. The cannabinoids yield mono-DNS derivatives with the exception of cannabidiol which forms a bis-DNS derivative. The following solvent systems are satisfactory for separation of cannabinoids on silica gel A, benzene-acetone (9 1) B, cyclohexane-ethyl acetate (5 1) C, cyclohexane-acetone-diethylamine (20 4 1) and D, cyclohexane-acetone-triethylamine (20 4 1). The R f values of nine cannabinoids in the above solvent systems are given in Table 4.25. 

Despite the lack of controlled studies, there is evidence that cannabinoids are of therapeutic value in the treatment of tics in Tourette syndrome, the reduction of levodopa-induced dyskinesia in Parkinson s disease, and some forms of tremor and dystonia. 

The bulk of the endogenous urinary material occurs in the EIII extract. These endogenous matrix levels highlight the value of the Kanter extraction scheme in providing relatively clean extracts for analysis of the neutral and 11-oic cannabinoids. 

An earlier study on the ultraviolet absorption properties of the cannabinoids performed in our laboratory gave reason to predict that HPLC-UV analysis of these compounds might be feasible. As shown in Figure 3, this reassessment of ultraviolet spectral properties of I-IV clearly demonstrated a preponderance of absorption characteristics of I at 212 nm as contrasted to 273.7 nm used in our earlier work. Literature values had been reported for absorption patterns of I (15),... 

Indeed, the nature of the sample seems to be a critical parameter in the reproducibility equation. Short-term and long-term reproducibility of retention times and peak areas for CEC separation of cannabinoids have been measured by Lurie et al. [66]. The RSDs (seven replicates) for retention times are around 0.5% for short-term and vary from 1.49% to 2.03% for the long-term study, while peak areas showed up to 39% variation. Significantly improved reproducibility values were obtained when one compound, cannabinol, was used as a reference. The RSDs for relative peak areas varied from 2.3% to 3.95% for short-term and 1.65% to 8.1% for the long-term study. 

While the SAR of the classical cannabinoids for CB] are well known, those for CB2 have not yet been thoroughly exploited. The few reports published so far indicate that the structural requirements for binding to CB2 differ very much from those of CB. Gareau et al. reported that the dimethyl-heptyl homologue (17a) of zf8-THC binds to both CBi and CB2 (Kj values... 

Numerous cannabinoids, anandamides and heterocyclics have been compared for CBj and CB2 binding [87], Most compounds did not differ significantly in their binding values for the two receptors except the specific CBj antagonist SR141716A (see below) which binds weakly to CB2 and the indole compound JWH-015 (20) which showed a CBj/CB2 binding ratio of 27.75. Busch-Petersen etal. synthesized a series of cannabinoids in which rotation around the Cj -C2 bond was blocked [102]. The compound with the cis-heptene side-chain (21) had the highest affinity for CBj (0.89 [iM) with the widest separation between CBj and CB2 affinities. Pertwee et al. showed... 

Now the whole trick of this procedure is the following. Prior to PCA, artificial compounds (or a real set of reference compounds) are added to the data matrix X. These additional data points (library spikes ) have coordinates that represent idealized properties of the library. For example, if the aim is to generate a library for the cannabinoid receptor family, possible coordinates of the idealized artificial compound might be 1 for drug-likeness, 1 for GPCR-ligand-likeness, 1 for cannabinoid-likeness, 0 for dopamine-likeness, 0 for kinase-inhibitor-likeness, and so forth. In this example, the value T indicates the maximum value of a property (presence of a feature), 0 indicates minimum values (absence of a feature). Of course, appropriate prediction models must be at hand. 

The stronger the interaction between the analyte and the cannabinoid, then the more strongly the material will be retained on the silica gel, thus resulting in a lower Ri value. 

The above results show that it is possible to achieve complete dissociation between cannabimimetic effect and analgetic action.These preliminary results may be of considerable therapeutic value because cannabinoids generally lack many of the side effects of opiates, such as high addiction liability and respiratory depression. 

Cannabis is undoubtedly one of the world s most remarkable plants. Virtually every part of it has been used and valued at one time or another. Its roots have been boiled to make medicine its seeds have been eaten as food by both animals and men, been crashed to make industrial oils, and been thrown onto blazing fires to release the minute intoxicating cannabinoids within the fibers along its stem have been prized above all others because of their strength and durability and its resin-laden leaves have been chewed, steeped in boiling water, or smoked as a medicine and an intoxicant. 

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