Non-classical cannabinoids

Non-classical Cannabinoids Endocannabinoid Derivatives Indole and its Derivatives... 

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]. 

A fourth important pharmacophoric element was established for the non-classical cannabinoid series in the form of a southern aliphatic hydroxyl group. Addition of this group to (192) resulted in the high-affinity CBi and CB2 receptor full agonist CP 55,940 (193) [129, 133], the tritiated form of which was used to first demonstrate specific cannabinoid binding sites in brain tissue [134]. Its enantiomer, CP 56,667 (194) has lower affinity for the CBi receptor (Table 6.17). 

A number of new scaffolds unrelated to the classical/non-classical cannabinoids and AAIs have been reported in the literature to deliver cannabinoid agonists. 

An additional pharmacophore introduced in the nonclassical cannabinoid series is the southern aliphatic hydroxyl (Makriyan-nis, 1990). A variation involves the highly potent classical/non-classical cannabinoid hybrids (e.g., 4, AM919) (Drake, 1998). 

Besides the classical cannabinoids there are other structural classes with cannabinoid activity the non-classical cannabinoids typified by CP-55,940 and the aminoalkylindols exemplified with WIN 55,212-2. The 1H-pyrazole-3-carboxylic acid amide derivatives SR 141716A (Rinaldi-Carmona et al., 1994) and SR 144528 (Rinaldi-Carmona et al., 1998) were discovered to be moderately selective cannabinoid receptor antagonists. 

There are two major groups of synthetic compounds which have cannabin-oid activity, but which differ chemically from the tricyclic THC-like canna-binoids the bicyclic cannabinoids, exemplified by compound CP55940 (23), and the (aminoalkyl)indoles exemplified by pravadoline (24a). A detailed SAR analysis of these groups of compounds is beyond the scope of this review. The bicyclic cannabinoids and derivatives have been reviewed previously [105] recent publications deal mainly with related tricyclic non-classical cannabinoids [106] and with the (aminoalkyl)indoles [92, 107]. It is of interest to note that while the bicyclic cannabinoids were originally prepared as simplified cannabinoids, the cannabinoid-type activity of the (ami-noalkyl)indoles was discovered by serendipity. These compounds were synthesized in a project aimed at the discovery of novel nonsteroidal anti-inflammatory agents presumably based on the indomethacin structure. However, while they did not possess anti-inflammatory properties, they were found to be antinociceptive, and to inhibit the electrically evoked contractions in a mouse vas deferens muscle preparation. This led to binding experi-... 

The best CB2-selective agonists to have been developed to date are all non-eicosanoid cannabinoids (Howlett et al. 2002 Ibrahim et al. 2003 Pertwee 1999a). They include the classical cannabinoids, L-759633, L-759656 and JWH-133, the non-classical cannabinoid HU-308, and the aminoalkylindole AM1241 (Figs. 5,6 and 7). All these ligands bind more readily to CB2 than to CBi receptors (Table 2) and have also been shown to behave as potent CB2-selective agonists in functional bioassays (Hanus et al. 1999 Ibrahim et al. 2003 Pertwee 2000 Ross et al. 1999a). 

Shim JY, Welsh WJ, Howlett AC (2003) Homology model of the CBI cannabinoid receptor sites critical for non-classical cannabinoid agonist interaction. Biopolymers 71 169-189... 

The southern aliphatic hydroxyl (SAH) pharmacophore is absent in the naturally occurring cannabinoids. To study more precisely the stereochemical requirements of this new pharmacophore, Makriyannis and co-workers designed a group of hybrid ligands that incorporated all of the structural features of both classical and non-classical cannabinoids (Drake et al. 1998 Tins et al. 1995,1994). 

The classical/non-classical cannabinoid hybrid AM4030 was resolved using chiral AD columns (Thakur et al. 2002).The (-)-isomer AM4030a has the (6S, 6aR, 9R, lOaR) stereochemistry and binds to CBi with subnanomolar affinity. The affinity of AM4030a was 158 times higher than that of its (-h)-isomer AM4030b. 

Gatley SJ, Lan R, Pyatt B, Gifford AN, Volkow ND, Makriyannis A (1997) Binding of the non-classical cannabinoid CP-55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors. Life Sci 61 L191-197... 

Johnson MR, Melvin LS (1986) The discovery of non-classical cannabinoid analgesics. In Mechoulam R (ed) Cannabinoids as therapeutic agents. CRC Press, Boca Raton, pp 121— 145... 

Tius MA, HUI WA, Zou XL, Busch-Petersen J, Kawakami JK, Fernandez Garcia MC, Drake DJ, Abadji V, Makriyannis A (1995) Classical/non-classical cannabinoid hybrids stereochemical requirements for the southern hydroxyalkyl chain. Life Sci 56 2007-2012... 

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. 

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