Biased versus Partial Agonism in the Search for Safer Opioid Analgesics.
Biased versus Partial Agonism in the Search for Safer Opioid Analgesics.
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DOI：
10.3390/molecules25173870
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发表时间：
2020-08-25
期刊：
影响因子：
--
通讯作者：
Calò G
中科院分区：
文献类型：
--
作者：
Azevedo Neto J;Costanzini A;De Giorgio R;Lambert DG;Ruzza C;Calò G
阿片类药物，如吗啡，作用于mu阿片受体，是治疗中重度疼痛的主要药物，在这些适应症中具有良好的疗效。然而，这些药物产生过多的不良反应，包括呼吸抑制，便秘，免疫抑制和长期治疗，耐受性，依赖性和滥用的危险。对β-抑制素2基因敲除（βarr2(−/−)）动物的研究表明，吗啡的镇痛作用增强，而副作用减少，这表明偏离抑制素的药物可能表现为副作用减少。然而，关于吗啡对βarr2（−/−）小鼠便秘和呼吸作用的改善，在这一领域存在争议。此外，用g蛋白偏向性mu受体进行基因工程的小鼠进行的研究表明，这些动物对阿片类药物的镇痛作用和副作用都增加了敏感性。一些新的分子已被鉴定为mu受体g蛋白偏向性激动剂，包括核桃苷（TRV130）、PZM21和SR-17018。这些化合物提供了临床前数据，明显支持对G蛋白的偏爱，以及有效和更安全的镇痛药的遗传前提。最近有临床数据表明奥立偏啶被批准用于医院和其他受控环境的短期静脉注射。虽然这些数据令人信服，并为药物发现提供了一个潜在的基于新途径的靶点，但对这些有偏见的激动剂的行为的一个更简单的解释是围绕内在活动的差异。一项非常详细的研究比较了胆碱、PZM21和SR-17018（以及其他）在一系列检测中的表现，表明这些分子表现为部分激动剂。治疗指标与疗效有相关性，偏倚因子与疗效无相关性。如果有g蛋白的扩增，但没有阻滞素途径，那么效能降低的激动剂将表现出高水平的g蛋白活性和低水平的阻滞素活性或不存在；提供减少副作用或“明显偏见”的镇痛药。总的来说，目前的数据表明——我们支持——将偏向性激动作用归因于莫激动剂镇痛药的副作用减少的观点是谨慎的。
Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.
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DOI：
10.1038/npp.2015.201
发表时间：
2016-02
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
Hill R;Lyndon A;Withey S;Roberts J;Kershaw Y;MacLachlan J;Lingford-Hughes A;Kelly E;Bailey C;Hickman M;Henderson G
通讯作者：
Henderson G
mu 阿片受体 G 蛋白偏向激活和失活机制的计算见解
影响因子：
8.2
作者：
Cheng, Jian-xin;Cheng, Tao;Tang, Yun
通讯作者：
Tang, Yun
影响因子：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT
影响因子：
4.2
作者：
Kiguchi N;Ding H;Ko MC
通讯作者：
Ko MC
影响因子：
1.8
作者：
Gan, T. J.;Wase, L.
通讯作者：
Wase, L.