Cannabinoid ligand classical

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 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). 

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). 

Nadipuram AK, Krishnamurthy M, Ferreira AM, Li W, Moore BM (2003) Synthesis and testing of novel classical cannabinoids exploring the side chain ligand binding pocket ofthe CBI and CB2 receptors. Bioorg Med Chem Lett 11 3121-3132... 

The principal agent responsible for these effects is A -tetrahydrocannabinol (A -THC), the major psychoactive component of Cannabis sativa. /1 -THC can interfere, not only with the activity of classical neurotransmitters but also with the activity of the endogenous cannabinoid system itself. Different studies support a role for this system in brain development and maturation, and several of its components have been characterized (receptors, endogenous ligands, and metabolism pathways). The effects of /1 -THC were caused by the activation of cannabinoid receptors, which emerge early in the developing brain (Ferndndez-Ruiz et al. 1992, 1994,1996,1999, 2000). 

However, studies on structure-activity relationships have revealed that, in addition to classical cannabinoids, other structurally different compounds can also be CB receptor ligands. Thus, the term cannabinoids is now applied to any compound with good affinity for cannabinoid receptors. 

Synthesis of Cannabinoid Receptor Ligands Approaches and Methods 3.1. Classical Cannabinoids and Covalent Binding Probes... 

Due to its lipidic nature, anandamide is barely soluble in water. In this case, it is impossible for the neurotransmitter to bind to a solvent-exposed area of its receptor, as schematized for classical neurotransmitter/receptor couples (Fig. 5.5). Instead, the ligand-binding domain of anandamide receptors (e.g., the cannabinoid receptor CBl in the brain) is made from a cluster of transmembrane helices. To reach this intramembrane binding site, anandamide has to penetrate the lipid bilayer before binding to the transmembrane embedded helices of the receptor. The molecular details of this intriguing mechanism are described in Section 5.2. 

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