Classical cannabinoids

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

CB2 Selective Classical Cannabinoids Indoles and Indazoles Resorcinol Derivatives Benzo[c]Chromen-6-one Derivatives... 

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 dithiolane group in the I -position has been shown to be at least as effective as the l, T-dimethyl group in enhancing the binding affinity of the classical cannabinoids, as can be seen by comparing compounds (123) and (124) with compounds (83) and (85). However, the constrained dithiolane compounds (125-127) showed decreased activity compared to their l, T-dimethyl analogues (99-101). In contrast to its l, T-dimethyl and ketone analogues, (117) and (119), the phenyl dithiolane compound (128) does not exhibit any CB2 selectivity. 

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. 

In addition, anandamide was found to parallel classical cannabinoid pharmacology in a series of nonbehavioral experimental systems. In isolated MVD, (Pertwee, 1992) and guinea pig ileum, it inhibited electrically evoked twitch responses (Pertwee, 1995). Moreover, anandamide was shown to decrease intraocular pressure in rabbits (Pate, 1995), to reduce sperm-fertilizing capacity in sea urchins by inhibition of the acrosome reaction (Schuel, 1994), and to produce hypotension in rats (Varga, 1995). 

Classical cannabinoids (CCs) are tricyclic terpenoid derivatives bearing a benzopyran moiety. This class includes the natural product (-)-delta-nine-tetrahydrocannabinol (Fig. 8, 1) and the other pharmacologically active constituents of the plant Cannabis sativa. 

Many classical cannabinoid analogs have been synthesized and evaluated pharmacologically and biochemically (Razdan, 1986 Mechou-lam, 1999). The CC structural features that seem to be important for cannabimimetic activity (Makriyannis, 1990) are as follows ... 

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). 

Xie X-Q, Eissentat M, Makriyannis A. Common cannabimimetic phar-macophoric requirements between aminoalkylindoles and classical cannabinoids. Life Sci 1995 56 1963-1970. 

Discriminative stimulus effect. Rhesus monkeys, trained to discriminate A-9-THC from vehicle in a two-lever drug discrimination procedure, were tested with a variety of psychoactive drugs, including cannabinoids or drugs from other classes. The results indicated that A-9-THC discrimination showed pharmacological specificity, in that none of the noncannabinoid drugs fully substituted for A-9-THC. The classical cannabinoids, A-9-THC and A-8-THC, and the novel cannabinoids, WIN and l-butyl-2-methyl-3-(l-naphthoyl)indole, produced full dose-dependent substitution for A-9-THC in all monkeys. A heptyl indole derivative failed to substitute for A-9-THC, but it also did not displace pH] CP-55,940 from its binding site . ... 

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. 

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],... 

While the SAR of the classical cannabinoids for CB] are well known, those for CB2 have not yet been thoroughly exploited. The few reports published so far indicate that the structural requirements for binding to CB2 differ very much from those of CB. Gareau et al. reported that the dimethyl-heptyl homologue (17a) of zf8-THC binds to both CBi and CB2 (Kj values... 

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-... 

Nonclassical cannabinoids consist of bicyclic and tricyclic analogues of A -THC that lack a pyran ring examples include CP55940, CP47497, CP55244 and HU-308 (Fig. 6). They are, therefore, closely related to the classical cannabinoids. 

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). 

Krishnamurthy M, Ferreira AM, Moore BM (2003) Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids. Bioorg Med Chem Lett 13 3487-3490... 

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