2-position of the indole had a marked effect on binding, with affinity dropping up to 19-fold (cf. (282) and (285)).
The high binding affinities obtained for the unsubstituted indole compounds thus support the hypothesis that H-bonding may not be the main binding feature of the AAIs and potentially aromatic stacking may be the dominant interaction. To explain the sudden drop in potency for the 2-methyl substituted indoles, the authors initiated a molecular modelling and receptor-docking study. From this study, they conclude that the loss in binding affinity is due to the loss of an aromatic stacking interaction .
More recently, the utility of the indole group as a scaffold for cannabinoid agonists has been demonstrated by a number of new patent applications appearing in the literature (286)-(290) [187-190]. Of particular note is compound (286) that is reported to have 18-fold selectivity for the CB1 receptor (CB1: Ki = 0.08 nM; CB2: Ki = 1.44 nM). In addition to the indole scaffold, a number of patent applications by AstraZeneca claim indole-like scaffolds such as benzimidazoles (289) [191-193] and azaindoles (290) . Although these compounds bind to both CB1 and CB2 receptors, the inventors claim that they may be useful in treating diseases without the associated CNS side effects.
Pyrrole and its derivatives
In Huffman's  overlay model of the classical cannabinoids and AAIs, the benzenoid portion of the indole ring did not participate in the overlap and only the pyrrole ring was involved. In order to investigate this, a homologous series of pyrroles was prepared and their pharmacology examined (see Table 6.26). In analogy to the indoles, the best results were obtained with the n-pentyl analogue (295), although this compound was approximately 10-fold less potent than its indole analogue.
Following on from this Tarzia et al.  designed and synthesised a range of pyrrole compounds based on the Huffman overlay. A range of substituents was explored around the pyrrole ring, the selections are detailed in Table 6.27. As seen with the AAIs, replacement of the naphthyl moiety with a monocyclic aromatic ring was detrimental to affinity. In particular, replacement with a phenyl ring resulted in complete loss of activity (299). A similar result was seen when the naphthyl moiety was replaced with an aliphatic chain (301). Replacement of the ketone group with an amide is tolerated, albeit with a loss in binding affinity. In addition, depending on the
Table 6.26 PYRROLE DERIVATIVES - N-1 ALKYL CHAIN SUBSTITUENTS 
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