Strategies to develop selective CB₂ receptor agonists from indole carboxamide synthetic cannabinoids

Activation of the CB₂ receptor is an attractive therapeutic strategy for the treatment of a wide range of inflammatory diseases. However, receptor subtype selectivity is necessary in order to circumvent the psychoactive effects associated with activation of the CB₁ receptor. We aimed to use potent, non-selective synthetic cannabinoids designer drugs to develop selective CB₂ receptor agonists. Simple structural modifications such as moving the amide substituent of 3-amidoalkylindole synthetic cannabinoids to the 2-position and bioisosteric replacement of the indole core to the 7-azaindole scaffold are shown to be effective and general strategies to impart receptor subtype selectivity. 2-Amidoalkylindole 16 (EC₅₀ CB₁ > 10 μM, EC₅₀ CB₂ = 189 nM) and 3-amidoalkyl-7-azaindole 21 (EC₅₀ CB₁ > 10 μM, EC₅₀ = 49 nM) were found to be potent and selective agonists with favourable physicochemical properties. Docking studies were used to elucidate the molecular basis for the observed receptor subtype selectivity for these compounds.