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[113] [107] [113] [107] [113] [107] [113] [107] [107] [113] [107] [113] [107] [113] [107] [113] [107] [113] [107] [113] [107] [113] [107] [113] [107]

1',1'-dimethyl cycloalkyl side-chain analogues of (99-101) were found to have in vitro activity similar to their straight-chain analogues (83), (85) and (91), respectively. However, there was no trend of increasing CB1 receptor-binding affinity with increasing ring size to mirror the effect of increasing chain length in the open-chain series [97].

Compounds with cis double bonds in the side chain were in general found to be more potent and efficacious than their triple-bond congeners, both in in vivo and in in vitro functional assays [98, 106, 107]. QSAR models have been generated for the compounds with unsaturated [108] and 1',1'-dimethyl [96] side chains to determine more precisely the pharmacophoric requirements of the receptor. It is postulated that for optimum potency, the side chain must be of a suitable length and flexibility to have the ability to loop back so that its terminus is in proximity to the phenolic ring. The widely used, potency enhancing 1'- and 2'-methyl substituents would be expected to increase the tendency of the side chain to adopt a looped back, rather than an extended conformation.

Aromatic rings are also tolerated in the side chain, as demonstrated by Krishnamurthy et al. [109]. The 1',1'-dimethylbenzyl compound (117) showed higher binding affinity than the simple benzyl compound (116). Compound (117) also showed around 13-fold selectivity for CB2 over CB1 binding.

A range of different functional groups has been introduced into the 1'-position of the C3 side chain, as shown in Table 6.10. A number of different functionalities were shown to be tolerated in this position, with lipophilic groups such as methyl and dithiolane being preferred over polar groups such as ketones and alcohols. Ketone (118) had similar CB1 receptor affinity to the unfunctionalised n-heptyl compound (84), while alcohol (120) had lower affinity. The phenyl ketone (119) had lower CB1 receptor affinity than the simple benzyl-substituted compound (116), but higher CB2 affinity, with about 12-fold selectivity for CB2 over CB1.

A dithiolane group in the 1 '-position has been shown to be at least as effective as the 1',1'-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 1',1'-dimethyl analogues (99-101). In contrast to its 1',1'-dimethyl and ketone analogues, (117) and (119), the phenyl dithiolane compound (128) does not exhibit any CB2 selectivity.

Surprisingly, an iodo substituent in the 1'-position was not well tolerated, suggesting that this substituent had an unfavourable interaction with the receptor or a detrimental effect on the conformation of the side chain [110].

A range of 1-substituted A8-THC, A9-THC and A6a'10a-THC derivatives, including many of those in Tables 6.9 and 6.10 has been disclosed in a patent application by Moore et al. [111]. The compounds are described as either agonists or antagonists of the CB1 and/or CB2 receptors. The in vivo activity of (1-cyclohexyl-1-methyl) ethyl compound (100) in a rat haemorrhagic shock model and the in vitro cytotoxic effects of the 1',1'-dimethylbenzyl compound (117) against glioma cells are described.

Halogen, cyano, carboxylic acid and amide functional groups have been introduced at the terminus of the C3 side chain, as shown in Table 6.11. This area of the molecule seems to be tolerant to both lipophilic and more polar groups. Halogen substitution at the terminal carbon of the side chain led to enhancement of affinity, with the bulkier halogens, bromine and iodine, producing the largest effects [110, 112]. The less lipophilic 5-cyano-1', 1'-dimethylpentyl and 5-(N,N-dimethyl-carboxamido)-1',1'-dimethylpentyl compounds (141) and (147) showed high affinity and in vivo potency similar to the 5-bromo-1',1'-dimethylpentyl compound (137). However, the cyanohydrin compound (143) showed decreased affinity and potency. This may indicate less tolerance for a hydrogen bond donor in this position. The corresponding carboxylic acid (146) showed very low binding affinity at CB1, but retained affinity at CB2. The piperidine hydrazide compound (149) exhibited high binding affinity despite the presence of a hydrogen bond donor. In this case, the hydrogen bond donor was separated by a longer linker group from the tricyclic core.

Chloro- and sulfonamide-substituted aromatic amides showed decreased binding affinity and in vivo potency compared to the simple aliphatic amides. Side chains with an additional (CH2)1-2 linker between the amide and the phenylsulfonamide group resulted in partial or absent in vivo effects [113]. The (CH2)-linked compound, (153), showed around 80-fold selectivity for CB2 over CB1 binding [107].

A number of compounds have been prepared that contain both a double or triple bond and a terminal functional group in the side chain [98, 107, 114]. In general, the combined modifications reinforced the SAR trends seen for the individual modifications.

C9 Substituent modifications

A major route of metabolism for (67) and (73) is oxidation at the C9 position to form hydroxymethyl and carboxyl metabolites. The hydroxymethyl metabolites are potent CB1 agonists with pharmacological profiles similar to the parent compounds, while the carboxy metabolites have reduced activity [115]; the 9-carboxy analogue of (73) does not bind to the CB1 receptor [93].

Table 6.12 A8-THC C9 SUBSTITUENTS

Cpd.

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