7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as Selective CB2 Cannabinoid Receptor Ligands: Structural Investigations around a Novel Class of Full Agonists

Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo- [1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB2 receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20: hCB2 Ki = 2.5 nM, SI = 166; 21: hCB2 Ki = 0.81 nM, SI = 383; 38: hCB2 Ki = 15.8 nM, SI > 633; 56: hCB2 Ki = 8.12 nM, SI > 1231; (R)-58: hCB2 Ki = 9.24 nM, SI > 1082). The effect of a chiral center on the biological activity was also investigated and it was found that the (R)-enantiomers exhibited greater affinity at the CB2 receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series behaved as agonists, exhibiting functional activity at the human CB2 receptor.