Table 6.8 shows the simple alkyl side-chain modifications of (67). The binding affinity of these analogues increases with increasing side-chain length, from butyl up to octyl. Methyl substituents in the 1'- and 2'-positions of the side chain have a beneficial effect on CB1 receptor affinity and in vivo potency, as previously shown by Adams. Huffman et al. [94] further demonstrated that methyl substitution in the 3'-position resulted in compounds with comparable binding affinity to the parent compound, while methyl substitution in the 4'-position decreased binding affinity. A trend similar to that seen for the pentyl side chain was observed for monomethyl substitution on the heptyl side chain (data not shown) [95]. Reduced CB1 binding affinity was seen for compounds with 1' ,1'-dimethyl-substituted side chains longer than octyl (92-95). These compounds also showed reduced, or no in vivo activity [96].

Compounds with conformationally restrained side chains, unsaturated side chains and aromatic side chains have been synthesised in order to better define the steric requirements of the binding site in the side-chain region. These are shown in Table 6.9. On average, the conformationally restrained


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