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. © 2012 American Chemical Society.
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
Ruggiero E.;
2012
Abstract
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. © 2012 American Chemical Society.
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