Cannabinoid receptor ligands groups

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). 

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. 

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... 

Mechoulam s group assumed that the presence of a specific caimabinoid receptor indicated the existence of endogenous specific caimabinoid ligands that activate these receptors. Taking into consideration that all plant cannabinoids are lipophilic components, they looked for lipophilic components of porcine brain that bind to the cannabinoid receptor. Indeed, in 1992 they identified the first endogenous cannabinoid (Devane et al., 1992), arachidonoyl ethanolamide, which was named anandamide (Figure 1) based on the Sanskrit word ananda, meaning bliss, as well as on its chemical nature, amide. 

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