Delineating the role of serotonin 5-HT2 receptors in opioid use disorders:Development of novel 5-HT2 modulators with translational studies in rodents andprimates

描述血清素 5-HT2 受体在阿片类药物使用障碍中的作用:通过啮齿类动物和灵长类动物的转化研究开发新型 5-HT2 调节剂

基本信息

  • 批准号:
    10164749
  • 负责人:
  • 金额:
    $ 60.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-01 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

This application responds to PA-18-058 to address the epidemic levels of prescription opioid abuse and addiction that have resulted in an appalling number of overdose deaths. Unequivocally, there is an urgent need for effective pharmacologic treatment options for opioid use disorder (OUD) that are safe, non-addictive, and without substantial diversion liability to address the national public health emergency. Compelling evidence suggests that serotonin (5HT) 2A and 2C G protein-coupled receptor (GPCR) subtypes may provide a fruitful strategy to achieve this goal. In this regard, 5HT2C agonists can reduce self-administration and block relapse-related drug- seeking behavior in rodents and monkeys. This has prompted development of 5HT2C-specific agonists that are devoid of potentially deleterious effects mediated through activation of the 5HT2A (i.e., hallucinogenic) and 5HT2B (i.e., cardiotoxic) subtypes. Furthermore, 5HT2C-specific agonists are required to delineate the roles of 5HT2 receptor subtypes in substance use disorders. To this end, our medicinal chemistry program has produced 4- phenyl-2-aminotetralin (PAT) analogs with unique multifunctional pharmacology at 5HT2 GPCRs, i.e., activation of 5HT2C signaling with inactivation of 5HT2A and 5HT2B signaling in the same monovalent, orally bioavailable, small molecule. Our preliminary results indicate the unique PAT-type 5HT2 pharmacology translates effectively in models of OUD in rhesus monkeys, including, attenuation of heroin-primed reinstatement, suggesting efficacy for addressing relapse. PATs do not have stimulant or sedative effects and are without liability for addiction, encouraging us to pursue translational studies in nonhuman primates (NHP) to guide development of PAT-type 5HT2 modulators as pharmacologic intervention for prescription and illicit opioid abuse, as well as, delineate 5HT2 roles in OUD. The overarching hypothesis tested is that an optimal balance of PAT function at 5HT2A receptors (inverse agonism/antagonism, partial agonism) relative to agonist function at 5HT2C receptors (implicit is no activation of 5HT2B) translates to beneficial effects in primate models of OUD. In Aim 1A medicinal chemistry and Aim 1B molecular pharmacology studies we will develop PAT analogs with a range of functional activities, potencies, and efficacies at 5HT2 receptors, including 5HT2C-specific agonists with 5HT2A inverse agonism. In Aim 2A we will assess the PATs for in vivo potency and efficacy at 5HT2A and 5HT2C receptors to establish dosing parameters for NHP studies. Aim 2B studies will use drug discrimination studies to evaluate in vivo 5HT2 activity in squirrel monkeys. Aim 3 will assess PATs for safety and efficacy to attenuate oxycodone and fentanyl self-administration as well as drug- and cue-primed reinstatement in squirrel monkeys. Results will establish the role of serotonergic 5HT2 receptors in the pathophysiology and pharmacotherapy of OUD. PATs that selectively block responding for drug self-administration and have appropriate safety and efficacy parameters including with regard to relapse will be considered for development in collateral future studies in collaboration with an identified interested pharma.
此应用程序响应PA-18-058,以解决处方阿片类药物滥用和成瘾的流行程度 这导致了数量惊人的服药过量死亡。毫无疑问,迫切需要有效的 阿片类药物使用障碍(OUD)的药物治疗选择是安全的、不会上瘾的 应对国家突发公共卫生事件的重大转移责任。令人信服的证据表明 5-羟色胺(5-羟色胺)2A和2C G蛋白偶联受体(GPCR)亚型可能为 实现这一目标。在这方面,5HT2C激动剂可以减少自我给药,阻止复发相关的药物- 在啮齿动物和猴子身上寻找行为。这促使了5HT2C特异性激动剂的开发,这些激动剂 没有通过激活5HT2a(即致幻)和5HT2b介导的潜在有害影响 (即,心脏毒性)亚型。此外,需要5HT2C特异性激动剂来描述5HT2的作用 物质使用障碍中的受体亚型。为此,我们的药物化学项目产生了4- 苯基-2-氨基四氢呋喃(PAT)类似物在5HT2 GPCRs上具有独特的多功能药理作用,即激活 5HT2C信号和5HT2a和5HT2b信号失活的同一单价,口服生物利用度, 小分子。我们的初步结果表明,独特的PAT-类型5HT2药理有效地翻译 在恒河猴的OUD模型中,包括对海洛因诱导的恢复的减弱,提示疗效 用来治疗旧病复发。PATS没有刺激或镇静作用,也没有上瘾的责任, 鼓励我们在非人灵长类动物(NHP)中进行翻译研究,以指导PAT类型的发展 5HT2调节剂作为处方和非法阿片类药物滥用的药理干预,以及描述 5HT2角色在OUD中。测试的最重要的假设是,在5HT2a处,PAT功能的最佳平衡 受体(反向激动型/拮抗型、部分激动型)与5HT2C受体的激动剂功能相关(隐含 是否激活5HT2b)在灵长类动物的OUD模型中转化为有益的效果。《目标1药物化学》 和目标1B分子药理学研究我们将开发具有一系列功能活性的PAT类似物, 5HT2受体的效力和有效性,包括具有5HT2A反向激动剂的5HT2C特异性激动剂。在……里面 目的:我们将评估PATS在5HT2A和5HT2C受体上的体内效力和有效性,以建立 NHP研究的剂量参数。目的2B研究将使用药物鉴别研究来评估体内5HT2 松鼠猴的活动。目标3将评估PATS用于减轻羟考酮和芬太尼的安全性和有效性 在松鼠猴子中,自我管理以及药物和线索启动的恢复。结果将确立 5-羟色胺能5HT2受体在慢性阻塞性肺疾病病理生理及药物治疗中的作用有选择地拍拍 阻断药物自我给药反应,并具有适当的安全性和有效性参数,包括 关于复发的问题,将考虑在未来的附属研究中与确定的 感兴趣的制药公司。

项目成果

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Raymond G. Booth其他文献

“Selective” serotonin 5-HTsub2A/sub receptor antagonists
选择性 5-羟色胺 5-HT2A 受体拮抗剂
  • DOI:
    10.1016/j.bcp.2022.115028
  • 发表时间:
    2022-06-01
  • 期刊:
  • 影响因子:
    5.600
  • 作者:
    Austen B. Casey;Meng Cui;Raymond G. Booth;Clinton E. Canal
  • 通讯作者:
    Clinton E. Canal
A novel 5HT2C-specific agonist/5HT2A-2B antagonist attenuates psychomotor behaviors induced by methamphetamine, oxycodone, and their combination
  • DOI:
    10.1016/j.drugalcdep.2014.09.497
  • 发表时间:
    2015-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Drake Morgan;Clinton E. Canal;Paul C. Orza;Jessica L. Rose;Myong S. Kim;Raymond G. Booth
  • 通讯作者:
    Raymond G. Booth

Raymond G. Booth的其他文献

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{{ truncateString('Raymond G. Booth', 18)}}的其他基金

Training Program on Development of Medications for Substance Use Disorder
药物滥用药物开发培训计划
  • 批准号:
    10630338
  • 财政年份:
    2022
  • 资助金额:
    $ 60.62万
  • 项目类别:
Training Program on Development of Medications for Substance Use Disorder
药物滥用药物开发培训计划
  • 批准号:
    10411562
  • 财政年份:
    2022
  • 资助金额:
    $ 60.62万
  • 项目类别:
Delineating the role of serotonin 5-HT2 receptors in opioid use disorders:Development of novel 5-HT2 modulators with translational studies in rodents andprimates
描述血清素 5-HT2 受体在阿片类药物使用障碍中的作用:通过啮齿类动物和灵长类动物的转化研究开发新型 5-HT2 调节剂
  • 批准号:
    10410391
  • 财政年份:
    2018
  • 资助金额:
    $ 60.62万
  • 项目类别:
Novel Functionally-Selective Serotonin 5HT2 Drugs for Amphetamines Abuse/Disorder
用于治疗安非他明滥用/疾病的新型功能选择性血清素 5HT2 药物
  • 批准号:
    8312648
  • 财政年份:
    2010
  • 资助金额:
    $ 60.62万
  • 项目类别:
Novel Functionally-Selective Serotonin 5HT2 Drugs for Amphetamines Abuse/Disorder
用于治疗安非他明滥用/疾病的新型功能选择性血清素 5HT2 药物
  • 批准号:
    8531900
  • 财政年份:
    2010
  • 资助金额:
    $ 60.62万
  • 项目类别:
Novel Functionally-Selective Serotonin 5HT2 Drugs for Amphetamines Abuse/Disorder
用于治疗安非他明滥用/疾病的新型功能选择性血清素 5HT2 药物
  • 批准号:
    8715749
  • 财政年份:
    2010
  • 资助金额:
    $ 60.62万
  • 项目类别:
Novel Functionally-Selective Serotonin 5HT2 Drugs for Amphetamines Abuse/Disorder
用于治疗安非他明滥用/疾病的新型功能选择性血清素 5HT2 药物
  • 批准号:
    8144930
  • 财政年份:
    2010
  • 资助金额:
    $ 60.62万
  • 项目类别:
Serotonin 5HT2C Agonist Drugs with 5HT2A/2B Antagonist Activity
具有 5HT2A/2B 拮抗活性的血清素 5HT2C 激动剂药物
  • 批准号:
    8231473
  • 财政年份:
    2008
  • 资助金额:
    $ 60.62万
  • 项目类别:
Serotonin 5HT2C Agonist Drugs with 5HT2A/2B Antagonist Activity
具有 5HT2A/2B 拮抗活性的血清素 5HT2C 激动剂药物
  • 批准号:
    8029498
  • 财政年份:
    2008
  • 资助金额:
    $ 60.62万
  • 项目类别:
Serotonin 5HT2C Agonist Drugs with 5HT2A/2B Antagonist Activity
具有 5HT2A/2B 拮抗活性的血清素 5HT2C 激动剂药物
  • 批准号:
    7769452
  • 财政年份:
    2008
  • 资助金额:
    $ 60.62万
  • 项目类别:

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Discovery of a High Affinity, Selective and β-arrestin Biased 5-HT7R Agonist
发现高亲和力、选择性和β-抑制蛋白偏向的 5-HT7R 激动剂
  • 批准号:
    10412227
  • 财政年份:
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  • 批准号:
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Supplement to Discovery of a high affinity, selective and beta-arrestinbiased 5-HT7R Agonist Grant
对高亲和力、选择性和 β 抑制偏向 5-HT7R 激动剂发现的补充补助金
  • 批准号:
    10799162
  • 财政年份:
    2022
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    $ 60.62万
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NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
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  • 批准号:
    6639179
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    2001
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    $ 60.62万
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NMDA RECEPTOR--AGONIST AFFINITY, EFFICACY/TRANSDUCTION
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全身麻醉药和 nAcCHOR 激动剂亲和力
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    6636512
  • 财政年份:
    2001
  • 资助金额:
    $ 60.62万
  • 项目类别:
General Anesthetics and nAcCHOR Agonist Affinity
全身麻醉药和 nAcCHOR 激动剂亲和力
  • 批准号:
    6326889
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    6266928
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  • 批准号:
    6539099
  • 财政年份:
    2001
  • 资助金额:
    $ 60.62万
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General Anesthetics and nAcCHOR Agonist Affinity
全身麻醉药和 nAcCHOR 激动剂亲和力
  • 批准号:
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