Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
J Med Chem. 2012 Jul 26;55(14):6608-23. doi: 10.1021/jm300763w. Epub 2012 Jul 11.
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.
大麻素受体激动剂作为炎症和神经性疼痛的潜在治疗靶点引起了关注。在这里，我们报告了一系列 7-氧代-[1,4]恶嗪并[2,3,4-ij]喹啉-6-甲酰胺衍生物的鉴定和优化，它们是一种新型的选择性大麻素 CB(2)受体激动剂的化学型。结构修饰导致了几种化合物作为有效的和选择性的大麻素受体激动剂的鉴定（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）。还研究了手性中心对生物活性的影响，发现（R）-对映体在 CB(2)受体上的亲和力大于（S）-对映体。在 3,5-环腺苷单磷酸测定中，该新系列表现为激动剂，在人 CB(2)受体上表现出功能性活性。
