Optimization of novel thioesters as a therapeutic strategy for combating opioid overdoses and abuse

优化新型硫酯作为对抗阿片类药物过量和滥用的治疗策略

基本信息

  • 批准号:
    10460546
  • 负责人:
  • 金额:
    $ 47.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

Abstract The current opioid crisis in the US is fueled by the availability and extreme potency of the synthetic opioids fentanyl, carfentanil and sufentanil. The major objective of this U-01 proposal is to optimize our lead thiolester candidate, D-cysteine ethyl ester (JMS-19) as a viable therapeutic agent to elicit a rapid and sustained reversal of opioid-induced respiratory depression (OIRD, a major cause of death) elicited by the potent synthetic opioids fentanyl, sufentanil and carfentanil, without eliciting withdrawal symptoms in opioid-addicted subjects. This work will involve a series of in silico, in vitro, ex vivo, and in vivo techniques that will first optimize the chemical structure of JMS-19 (i.e., produce a derivative with greater efficacy and chemical stability) and then determine the pharmacodynamics, pharmacokinetics, and safety for the lead compound, laying the groundwork for seeking FDA approval for studies in humans. An example flow of drug development will be D-CYSee to D- cysteine methyl ester (that we predict will be approximately 100 times more potent than D-CYSee) to S-nitroso (SNO)-D-cysteine methyl ester (we have established that SNO-D-cysteine ethyl ester is approximately 1,000 times more potent than D-CYSee) to S-ethyl-D-cysteine methyl ester and S-sulfinic-D-cysteine methyl ester (which we predict will be equally potent to the SNO-derivatives but much more chemically stable and resistant to enzymatic degradation). We will provide compelling evidence that JMS-19 reverses OIRD without eliciting any withdrawal symptoms in rats treated with morphine or fentanyl, and will provide key data, which strongly suggest that the primary mechanism of action for JMS-19 and the related thiolesters is by binding to and inactivating β-arrestins 1 and 2. These molecular key targets will allow us to optimize JMS-19 for maximum efficacy in silico and in vitro, for ultimate testing against the opioids in freely-moving male and female rats. This will combine molecular dynamics simulations which will optimize JMS-19's membrane permeability and binding to active β-arrestins 1 and 2. These computational results will be confirmed experimentally by means of hydrogen deuterium exchange mass spectrometry before the final pharmacodynamics data will be shared with the rest of the project. The in vivo studies will involve (1) testing D-CYSee and optimized structural analogues against fentanyl, carfentanil and sufentanil to determine in detail how out test thiolesters reverse the negative effects of the opioid on ventilatory timing and mechanics and arterial blood-gas chemistry in freely-moving male and female rats, and (2) combinations of fentanyl and methamphetamine, and often deadly (ventilatory- depressant) combination in humans. Finally, we will perform pharmacokinetic studies on at least one of the optimized D-CYSee derivatives to establish the temporal distribution of these compounds in the absence and presence of fentanyl in order to relate the efficacy of the thiolesters with the pharmacological reversal of OIRD. In summary, we are confident that our project will produce a series of active thiolesters with potent abilities to elicit rapid and sustained reversal of the OIRD elicited by potent synthetic opioids.
摘要 美国目前的阿片类药物危机是由合成阿片类药物的可用性和极端效力所推动的 芬太尼卡芬太尼舒芬太尼本U-01提案的主要目标是优化我们的铅硫酯 候选人,D-半胱氨酸乙酯(JMS-19)作为一种可行的治疗剂,以引起快速和持续的逆转 阿片类诱导的呼吸抑制(OIRD,死亡的主要原因)引起的强效合成阿片类药物 芬太尼、舒芬太尼和卡芬太尼,在阿片类药物成瘾受试者中不引起戒断症状。这 这项工作将涉及一系列的计算机、体外、离体和体内技术,这些技术将首先优化化学物质, JMS-19的结构(即,产生具有更大功效和化学稳定性的衍生物),然后确定 先导化合物的药效学、药代动力学和安全性,为 申请FDA批准进行人体研究药物开发流程的一个例子是D-CY到D- 半胱氨酸甲酯(我们预测其效力将比D-CYSee强约100倍)转化为S-亚硝基 (SNO)-D-半胱氨酸甲酯(我们已经确定SNO-D-半胱氨酸乙酯是约1,000 比D-CYSee效力高10倍)转化为S-乙基-D-半胱氨酸甲酯和S-亚磺酸-D-半胱氨酸甲酯 (我们预测其对SNO衍生物同样有效,但化学稳定性和耐受性更高 酶降解)。我们将提供令人信服的证据,证明JMS-19逆转OIRD,而不引发 任何戒断症状的大鼠与吗啡或芬太尼治疗,并将提供关键数据,这强烈 这表明JMS-19和相关硫醇酯的主要作用机制是通过结合并 使β-抑制蛋白1和2失活。这些分子关键目标将使我们能够优化JMS-19, 在计算机和体外的有效性,对自由移动的雄性和雌性大鼠的阿片类药物的最终测试。这 将结合联合收割机分子动力学模拟,优化JMS-19的膜渗透性和结合 活性β-抑制蛋白1和2。这些计算结果将通过实验得到证实。 在最终药效学数据共享之前, 项目的其余部分。体内研究将包括(1)测试D-CYSee和优化的结构类似物 对芬太尼,卡芬太尼和舒芬太尼,以确定详细如何测试硫醇酯逆转阴性 阿片类药物对自由运动时排尿时间、力学和动脉血气化学的影响 雄性和雌性大鼠,以及(2)芬太尼和甲基苯丙胺的组合,并且通常是致命的(镇静剂- 在人类中的组合。最后,我们将对至少一种药物进行药代动力学研究。 优化的D-CYSee衍生物,以建立这些化合物在不存在和 为了将硫醇酯的功效与OIRD的药理学逆转相关联,需要使用芬太尼。 总之,我们相信我们的项目将产生一系列具有强大能力的活性硫醇酯, 引起由强效合成阿片类药物引起的OIRD的快速和持续逆转。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Advances in D-Amino Acids in Neurological Research.
L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats.
  • DOI:
    10.3389/fphar.2023.1303207
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
  • 通讯作者:
Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences.
大鼠体积描记模型中海洛因和芬太尼引起的呼吸抑制:效力、耐受性和性别差异。
  • DOI:
    10.1124/jpet.122.001476
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Marchette,RenataCN;Carlson,ErikaR;Frye,EmmaV;Hastings,LyndsayE;Vendruscolo,JanainaCM;Mejias-Torres,Gustavo;Lewis,StephenJ;Hampson,Aidan;Volkow,NoraD;Vendruscolo,LeandroF;Koob,GeorgeF
  • 通讯作者:
    Koob,GeorgeF
Thoughts on the role of endogenous D-cysteine in neuronal function.
  • DOI:
    10.1002/bies.202200089
  • 发表时间:
    2022-07
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Seckler, James M.
  • 通讯作者:
    Seckler, James M.
Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.
  • DOI:
    10.1038/s41598-021-86458-x
  • 发表时间:
    2021-03-26
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Jenkins MW;Khalid F;Baby SM;May WJ;Young AP;Bates JN;Cheng F;Seckler JM;Lewis SJ
  • 通讯作者:
    Lewis SJ
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stephen john lewis其他文献

stephen john lewis的其他文献

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{{ truncateString('stephen john lewis', 18)}}的其他基金

Repurposing L-NAC to prevent fentanyl-induced respiratory depression
重新利用 L-NAC 预防芬太尼引起的呼吸抑制
  • 批准号:
    10641050
  • 财政年份:
    2023
  • 资助金额:
    $ 47.83万
  • 项目类别:
Optimization of novel thioesters as a therapeutic strategy for combating opioid overdoses and abuse
优化新型硫酯作为对抗阿片类药物过量和滥用的治疗策略
  • 批准号:
    10015761
  • 财政年份:
    2020
  • 资助金额:
    $ 47.83万
  • 项目类别:
Optimization of novel thioesters as a therapeutic strategy for combating opioid overdoses and abuse
优化新型硫酯作为对抗阿片类药物过量和滥用的治疗策略
  • 批准号:
    10227069
  • 财政年份:
    2020
  • 资助金额:
    $ 47.83万
  • 项目类别:
Functional Mapping of the afferent and Efferent Projections of the Superior Cervical Ganglion Interactome
颈上神经节相互作用组传入和传出投影的功能图
  • 批准号:
    9531826
  • 财政年份:
    2016
  • 资助金额:
    $ 47.83万
  • 项目类别:
Vagal afferent cell bodies as sensors of blood-borne factors
迷走神经传入细胞体作为血源性因子的传感器
  • 批准号:
    7878582
  • 财政年份:
    2007
  • 资助金额:
    $ 47.83万
  • 项目类别:
Vagal afferent cell bodies as sensors of blood-borne factors
迷走神经传入细胞体作为血源性因子的传感器
  • 批准号:
    7494583
  • 财政年份:
    2007
  • 资助金额:
    $ 47.83万
  • 项目类别:
Vagal afferent cell bodies as sensors of blood-borne factors
迷走神经传入细胞体作为血源性因子的传感器
  • 批准号:
    7263330
  • 财政年份:
    2007
  • 资助金额:
    $ 47.83万
  • 项目类别:
Vagal afferent cell bodies as sensors of blood-borne factors
迷走神经传入细胞体作为血源性因子的传感器
  • 批准号:
    7617543
  • 财政年份:
    2007
  • 资助金额:
    $ 47.83万
  • 项目类别:
BIOCHEMICAL MARKERS IN ADULT PATIENTS WITH ANEURYSMAL SUBARACHNOID HEMORRHAGE
动脉瘤性蛛网膜下腔出血成年患者的生化标志物
  • 批准号:
    7717128
  • 财政年份:
    2007
  • 资助金额:
    $ 47.83万
  • 项目类别:
ADVANCED NEUROMONITORING, AND BIOCHEMICAL MARKERS IN ADULT PATIENTS WITH ANEURY
成年动脉瘤患者的高级神经监测和生化标记物
  • 批准号:
    7605460
  • 财政年份:
    2006
  • 资助金额:
    $ 47.83万
  • 项目类别:

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