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

Abstract

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.