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.

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(2)K(i) = 2.5 nM, SI = 166; 21, hCB(2)K(i) = 0.81 nM, SI = 383; 38, hCB(2)K(i) = 15.8 nM, SI > 633; 56, hCB(2)K(i) = 8.12 nM, SI > 1231; (R)-58, hCB(2)K(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.

• Authors: Pier Giovanni Baraldi, Giulia Saponaro, Allan R Moorman, Romeo Romagnoli, Delia Preti, Stefania Baraldi, Emanuela Ruggiero, Katia Varani, Martina Targa, Fabrizio Vincenzi, Pier Andrea Borea, Mojgan Aghazadeh Tabrizi
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 14 Pg. 6608-23 (Jul 26 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22738271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Quinolines
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2

Topics

• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Drug Design
• Humans
• Inhibitory Concentration 50
• Ligands
• Quinolines (chemical synthesis, chemistry, metabolism, pharmacology)
• Rats
• Receptor, Cannabinoid, CB1 (agonists, metabolism)
• Receptor, Cannabinoid, CB2 (agonists, metabolism)
• Substrate Specificity