7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as Selective CB _2 cannabinoid receptor ligands: Structural investigations around a novel class of full agonists

摘要

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 CB _2 receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20, hCB _2K _i = 2.5 nM, SI = 166; 21, hCB _2K _i = 0.81 nM, SI = 383; 38, hCB _2K _i = 15.8 nM, SI > 633; 56, hCB _2K _i = 8.12 nM, SI > 1231; (R)-58, hCB _2K _i = 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 CB _2 receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as agonists, exhibiting functional activity at the human CB _2 receptor.