Design, Synthesis, and Pharmacological Characterization of Indole-3-ylacetamides, Indole-3-yloxoacetamides, and Indole-3-ylcarboxamides: Potent and Selective CB2 Cannabinoid Receptor Inverse Agonists

In our search for new cannabinoid receptor modulators, we describe herein the design and synthesis of three sets of indole-based ligands characterized by an acetamide, oxalylamide, or carboxamide chain, respectively. Most of the compounds showed affinity for CB2 receptors in the nanomolar range, with Ki values spanning 3 orders of magnitude (377−0.37 nM), and moderate to good selectivity over CB1 receptors. Their in vitro functional activity as inverse agonists was confirmed in vivo in the formalin test of acute peripheral and inflammatory pain in mice, in which compounds 10a and 11e proved to be able to reverse the effect of the CB2 selective agonist COR16