Cb2 agonists

Receptor subtype selective CB2 agonists are seen as potential candidates for the treatment of a variety of diseases, including pain-related indications. The promise of useful therapeutic effects without unwanted CNS side effects makes the development of CB2 selective compounds a particularly attractive proposition. Several classes of CB2 selective agonists, including classical cannabinoids, resorcinols, indoles, indazoles and other heterocyclic derivatives and their SAR studies have been reported.

cb2 selective classical cannabinoids

Of the three main pharmacophoric elements in the classical cannabinoid template discussed previously, the phenolic hydroxyl group at C1 has been shown to be the most important for CB2 selectivity. In 1996, a group at Merck Frosst [212] and the Huffman group [213] independently demonstrated that removal of this hydroxyl group in the 1',1'-dimethylheptyl series leads to compounds with high CB2 receptor affinity and between 8- and 40fold selectivity for CB2 over CB1 binding affinity (Table 6.30). The Merck Frosst paper further describes modification of the phenol to a methoxy group, resulting in higher CB2 selectivity [212].

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The CB2 receptor has been shown to tolerate shorter C3 side chains than the CB1 receptor and the Huffman group has exploited this in combination with C1 modifications to develop highly selective CB2 receptor ligands (Tables 6.31 and 6.32) [214, 215].

The 11-hydroxy analogues of the 1'1'-dimethyl compounds in Tables 6.31 and 6.32 were also prepared by the Huffman group. In general, these showed higher affinity for both CB1 and CB2 receptors than the simple methyl analogues, but reduced CB2 selectivity (data not shown) [215].

Table 6.30 1-DEOXY AND 1-METHOXY A8-THC DERIVATIVES

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Table 6.30 1-DEOXY AND 1-METHOXY A8-THC DERIVATIVES

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(85) AS-THC-DMH

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