Cannabinoid receptors classical cannabinoids

A -THC, the main psychoactive component of cannabis, is a moderately potent partial agonist of the CBi and CB2 receptors, while cannabidiol has little affinity for either receptor (Table 6.7). The term classical cannabinoids is used to describe cannabinoid receptor modulators structurally related to (67), which have a tricyclic dibenzopyran core. While several other structural types of cannabinoid receptor modulators have been discovered in recent years, the classical cannabinoids are still by far the most extensively studied group in terms of SAR and pharmacology. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

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). 

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. 

Anandamide was isolated from water-insoluble fractions of the porcine brain. It binds to CB1 with rather moderate affinity (Ki 61 nM) and a low affinity for the CB2 receptor (Ki 1930 nM). The name anandamide is based on its chemical nature (an amide) and the Sanskrit word ananda meaning bliss. The chemical structure of anandamide can be divided into two major molecular fragments a polar ethanolamido head group and a hydrophobic arachidonyl chain. The polar head group comprises a secondary amide functionality with an N-hydroxyalkyl substituent while the lipophilic fragment is a non-conjugated c/ s tetraolefinic chain and an n-pentyl chain reminiscent of the lipophilic side chain found in the classical cannabinoids. A number of anandamide analogs have been synthesized and demonstrated to have considerable selectivity for the CB1 receptor in comparison to the CB2 receptor. 

Despite the recent advances in molecular biology, the mechanisms of action and the physiological functions of the anandamide system remain obscure. It would appear that the cannabinoid receptors and the anandamides reside within the neurons. Thus unlike the classical neurotransmitters noradrenaline and serotonin, the anandamides are not released into the synaptic cleft and are not involved in intemeuronal communication. Instead the anandamides modulate the excitability and inhibitory responsiveness of neurons by acting on cannabinoid hetero-ceptors located on inhibitory and excitatory terminals. In this way, the... 

The term classical cannabinoids refers to tricyclic THC-type cannabinoids. The SAR in these series have been quite extensively investigated in the past and several reviews have appeared [21, 91, 92], The structure-activity requirements formulated have withstood the erosion of time. Most of the published work refers to in vivo tests for effects now assumed to be due to CBi activation. Compton et al. have recently correlated binding to CBi with in vivo activity and have concluded that the requirements for binding to the cannabinoid receptor correlate well with activity across different species, and that receptor binding mediates most of the pharmacological effects of cannabinoids [93],... 

In terms of chemical structure, established cannabinoid receptor agonists fall essentially into four main groups classical, nonclassical, aminoalkylindole and eicosanoid (reviewed in Howlett et al. 2002 Pertwee 1999a). 

Members of the eicosanoid group of cannabinoid receptor agonists have markedly different structures both from the aminoalkylindoles and from classical and nonclassical cannabinoids. Important members of this group are the endocannabinoids, arachidonoylethanolamide (anandamide), 0-arachidonoylethan-olamine (virodhamine), 2-arachidonoyl glycerol and 2-arachidonyl glyceryl... 

One recently developed synthetic cannabinoid receptor agonist that interacts almost as well with CB2 as with CBi receptors (Tables 1 and 2) is BAY 38-7271 (De Vry and Jentzsch 2002 Mauler et al. 2002, 2003). This compound has a structure that is not classical, non-classical, aminoalkylindole or eicosanoid (Fig. 9). 

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... 

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... 

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... 

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