Optimization of a 1,3,4-oxadiazole series for inhibition of Ca(2+)/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain.
Optimization of a 1,3,4-oxadiazole series for inhibition of Ca(2+)/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain.
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DOI：
10.1016/j.ejmech.2018.11.036
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发表时间：
2019-01-15
影响因子：
6.7
通讯作者：
Flaherty DP
中科院分区：
文献类型：
--
作者：
Kaur J;Soto-Velasquez M;Ding Z;Ghanbarpour A;Lill MA;van Rijn RM;Watts VJ;Flaherty DP
腺苷酸环化酶1型（AC 1）和腺苷酸环化酶8型（AC 8）是一类跨膜腺苷酸环化酶（AC），它们受Ca 2 +/钙调蛋白刺激。研究表明，AC 1缺失的小鼠具有减弱的炎性疼痛反应，而AC 1/AC 8双敲除小鼠显示出减弱的疼痛反应和阿片类药物依赖。因此，AC 1已成为治疗慢性疼痛和阿片类药物滥用的一个有前途的新靶点。我们发现1，3，4-恶二唑支架抑制稳定表达AC 1或AC 8的细胞中Ca 2 +/钙调素刺激的环腺苷酸（cAMP）产生。然后，我们进行了结构-活性关系研究，其中我们设计并合成了65种类似物，以调节细胞中相对于每种AC亚型的效力和选择性。此外，类似物到AC 1同源性模型的分子对接表明分子可以在ATP结合位点结合。最后，在炎性疼痛的小鼠模型中测试了优先类似物，并显示出适度的镇痛特性。总之，我们的数据表明，1，3，4-恶二唑代表了一种新的支架细胞抑制钙/钙调素刺激的AC 1-和AC 8 cAMP，并值得进一步探索作为潜在的先导化合物用于治疗慢性炎性疼痛。
Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca2+/calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1/AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits Ca2+/calmodulin-stimulated cyclic adenosine 3’,5’-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure-activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of Ca2+/calmodulin-stimulated AC1- and AC8 cAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain.
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