Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias.
Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias.
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DOI：
10.1021/acs.jmedchem.8b01136
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发表时间：
2018-10-11
影响因子：
7.3
通讯作者：
Bannister TD
中科院分区：
文献类型：
--
作者：
Kennedy NM;Schmid CL;Ross NC;Lovell KM;Yue Z;Chen YT;Cameron MD;Bohn LM;Bannister TD
虽然MU阿片受体(MOR)激动剂作为广谱止痛药特别有效，但要将止痛与许多有问题的副作用明确分离一直是非常困难的。最近，许多研究小组都在寻找可诱导最小的βarrestin介导信号的MOR激动剂，因为在2基因敲除小鼠中，经MOR激动剂治疗的β抑制被发现具有增强的抗伤害作用，呼吸抑制和快速反应明显减少。现在有大量的数据支持G蛋白信号偏向的MOR激动剂可以是有效的止痛药这一前提。我们最近发现，在一系列化学物质中，偏倚的程度与呼吸安全指数的大小呈线性相关。在这里，我们描述了哌啶苯并咪唑酮类MOR激动剂的合成和优化，这些激动剂一起显示出广泛的偏倚(G/βARR2)。我们确定了影响效力和最大化偏差的结构特征，并表明许多化合物具有理想的性质，如较长的半衰期和较高的脑渗透率。
While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal βarrestin-mediated signaling because MOR agonist-treated βarrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/βarr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.
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影响因子：
64.5
作者：
Schmid CL;Kennedy NM;Ross NC;Lovell KM;Yue Z;Morgenweck J;Cameron MD;Bannister TD;Bohn LM
通讯作者：
Bohn LM
通过反基因 RNA 下调 β-arrestin 2 增强吗啡镇痛并预防吗啡耐受
影响因子：
2.2
作者：
Bu, Huilian;Liu, Xijiang;Gao, Feng
通讯作者：
Gao, Feng
影响因子：
7.3
作者：
Choi JY;Calvet CM;Gunatilleke SS;Ruiz C;Cameron MD;McKerrow JH;Podust LM;Roush WR
通讯作者：
Roush WR
影响因子：
64.8
作者：
Matthes, HWD;Maldonado, R;Kieffer, BL
通讯作者：
Kieffer, BL
影响因子：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT