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The polar head group

The most extensive investigation of SAR has been carried out in this region of AEA. The following SAR has been established. In general, a secondary amide is optimal. The primary amide is inactive (227) and tertiary amides are less active than AEA or inactive (228), (229) [37, 150, 163]. The hydroxyl group is not required for activity and a wide range of replacements are tolerated such as hydrogen (230), small alkyl (231), halogen (232), (233), ether (234), phosphate (235) or aromatic (236) (see Table 6.20). In particular, the chloroethyl derivative (232) was shown to have 11-fold improved affinity compared to AEA.

The introduction of a methyl into the head group at the C1'-position and in particular the R-isomer (237) resulted in 4-fold higher affinity than AEA, while the S- isomer (238) had 2-fold lower affinity than AEA [48, 157], the R-isomer (237) was also resistant to enzymatic hydrolysis [157]. However, introduction of larger alkyl groups into the C1' position such as the i-butyl analogue (239) leads to a large drop in activity [155]. Methylation of the C2' position also leads to improved affinity compared to AEA. In particular, the R-isomer (240) has 4-fold enhanced affinity; this derivative is also stable to enzymatic hydrolysis by FAAH [48] (see Table 6.20).

Extension of the head group by insertion of a methylene group is tolerated, the N-propanol derivative (241) having a slight increase in binding affinity compared to AEA. Further extension of the carbon chain, such as the butyl derivative (242), led to a decrease in activity [150, 151].

Replacement of the ethanolamine head group is also well tolerated. Substitution with a cyclopropyl (243) [37], allyl (244) or propargyl group (245) [164] all led to an increase in binding affinity compared to AEA. Replacement of the head group with aromatics is also allowed. The phenyl derivative (246) retains affinity at the CB1 receptor [37], whereas the 2-substituted N-methyl pyrrole (247) has a 2-fold improved affinity compared to AEA [167]. Interestingly, the 3-substituted furan derivative (23) that has micromolar affinity for the AEA transporter (see above) does not bind to the CB1 receptor, but has good affinity for the CB2 receptor [167]. These results are summarised in Table 6.20.

Overall, these results suggest that the hydroxyl group is not vital for binding and that both hydrophobic and hydrophilic head groups can be accommodated. The cavity in which the head group binds is relatively small as only modest variations in this position lead to high-affinity lig-ands. With regard to CB2 selectivity, very few reports have looked in detail at the requirements for CB2 binding in AEA derivatives and most ligands synthesised to date have tended to be relatively selective for the CB1 receptor.

Table 6.20 AEA DERIVATIVES - THE POLAR HEAD GROUP SAR

4(CH2)3COR

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