Cannabinoid ligand groups

The identification of a specific cannabinoid receptor in the brain suggested the existence of a brain cannabinoid ligand. It seemed to us quite unacceptable that the brain will waste its energy to synthesize a receptor (in high concentrations) in order to bind a constituent of a plant. The only reasonable assumption which could be made was that the brain produces a neuronal mediator, a specific compound which binds to and activates the cannabinoid receptor. The plant cannabinoid, J9-THC, by structural coincidence happens to bind to the same receptor. In the late 1980 s, several groups initiated work aimed at the discovery of such a brain constituent. 

Khanolkar AD, Abadji V, Lin S, HUI WAG, Taha G, Abouzid K, Meng Z, Fan P, Makriyannis A (1996) Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand. J Med Chem 39 4515-4519... 

The cannabinoid ligand can be classified according to Ooms et al [43] into six groups i) classical, ii) nonclassical, iii) bicyclic, iv) aminoalkylindoles, v) endocannabinoid analogues, vi) diarylpyrazoles. Ooms et al [43] studied the pharmacophore of 3-alkyl-5-arylimidazolidinediones as a new CBi cannabinoid receptor. Thomas et al [44] have studied SAR data on a series of 1,5-diphenylpyrazoles proposing a pharmacophoric alignment of these compounds with THC... 

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). 

Researchers at Japan Tobacco (Osaka, Japan) reported the CB2 selective inverse agonist JTE-907, whose structure is characterized by the presence of a carboxamide group in the 3-position of a quinolone nucleus (66, Fig. 18) (Iwamura et al. 2001) with anti-inflammatory in vivo activity. Naphthyridine derivatives sharing some structural features of JTE-907 were recently reported as cannabinoid receptor ligands with a preference for the CB2 receptor (Ferrarini et al. 2004). 

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