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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6608-6623
• 全文大小：511K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

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, hCB₂K_i = 2.5 nM, SI = 166; 21, hCB₂K_i = 0.81 nM, SI = 383; 38, hCB₂K_i = 15.8 nM, SI > 633; 56, hCB₂K_i = 8.12 nM, SI > 1231; (R)-58, hCB₂K_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 CB₂ receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as agonists, exhibiting functional activity at the human CB₂ receptor.