Investigation of in vivo efficacy of G-protein biased mu opioid receptor agonists.

G 蛋白偏向 mu 阿片受体激动剂的体内功效研究。

• 批准号: 10654562
• 负责人: Loc M Pham
• 金额: $ 3.97万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654562
• 关键词: Absence of pain sensation; Adverse effects; Agonist; Analgesics; Animal Model; Behavioral; Biological Assay; Buprenorphine; Cessation of life; Clinical; Data; Development; Dose; Exhibits; Fentanyl; G-Protein Signaling Pathway; GTP-Binding Proteins; Health Sciences; In Vitro; Investigation; Measures; Mediating; Medical center; Methodology; Mississippi; Morphine; Neurosciences; Nociception; Opioid; Opioid agonist; Overdose; Oxycodone; Pain; Pain management; Pathway interactions; Pharmaceutical Preparations; Positioning Attribute; Pre-Clinical Model; Published Comment; Publishing; Rattus; Reinforcement Schedule; Reporting; Respiration; Safety; Self Administration; Series; Signal Pathway; Signaling Protein; Stimulus; Temperature; Testing; Therapeutic; Therapeutic Effect; Training; Universities; Ventilatory Depression; Whole Body Plethysmography; Work; abuse liability; antinociception; arrestin 2; behavior measurement; comparative; design; drug discovery; efficacious treatment; graduate school; improved; in vivo; mu opioid receptors; novel; pre-clinical; programs; recruit; relative effectiveness; respiratory; side effect; stem; warm temperature

PROJECT SUMMARY Typical mu-opioid receptor (MOR) agonists (e.g., oxycodone, fentanyl) are efficacious analgesics for the treatment of moderate to severe pain. However, the therapeutic window of typical MOR agonists for pain management is limited by their unwanted side effects such as respiratory depression and abuse liability. The limitations of typical MOR agonists have prompted the development of novel MOR agonists (e.g., PZM-21, SR- 17018) with more favorable safety profiles. However, the mechanism by which these novel agonists produce their more desirable behavioral effects is still unknown. One body of evidence indicates that the compounds exhibit improved side-effect profiles due to G-protein signaling bias. However, more recent work has challenged this position with evidence indicating that these novel agonists are merely partial agonists at the MOR. Thus, the results from in vitro investigations into mechanisms are conflicting and in vivo studies are lacking. The purpose of this proposal is to investigate a series of G-protein biased MOR agonists in preclinical models of therapeutic and side effects, and under experimental conditions designed to differentiate typical from partial MOR agonists. Under these conditions, typical MOR agonists produce maximal magnitude of effects, and partial MOR agonists produce sub-maximal magnitude of effects. Specifically, Aim 1 will measure the magnitude of analgesia produced by novel MOR agonists in comparison to typical and partial MOR agonists under different levels of thermal nociceptive stimulation in a hot-plate assay. Aim 2 will measure the magnitude of respiratory depression produced by novel MOR agonists, in comparison to typical and partial MOR agonists in a whole-body plethysmography assay. Aim 3 will compare the maximum breakpoint (indicator of abuse liability) mediated by typical, partial, and novel MOR agonists in a self-administration assay under increasing levels of operant challenge provided by a progressive-ratio schedule of reinforcement. Based on the profile of behavioral effects engendered by the novel MOR agonists, we will be able to determine which in vitro position is most closely recapitulated in vivo. Ultimately, our findings from these three aims will inform the development of opioid-based therapeutics with more favorable safety profiles and wider therapeutic windows. To accomplish these aims, the training plan was described in this proposal, and, it will be carried out at the Jackson campus of the University of Mississippi Medical Center. The applicant will be receiving scientific training and professional development from the sponsor, the sponsor's collaborators, the Program In Neuroscience, and the School of Graduate Studies in the Health Sciences.

项目总结 典型的MU阿片受体(MOR)激动剂(如羟考酮、芬太尼)是有效的止痛剂 治疗中度至重度疼痛。然而，典型的MOR激动剂治疗疼痛的窗口 管理受到其不良副作用的限制，如呼吸抑制和滥用责任。这个 典型MOR激动剂的局限性促进了新型MOR激动剂(例如PZM-21、SR-1)的开发。 17018)具有更有利的安全配置文件。然而，这些新型激动剂产生的机制 它们更令人满意的行为效果仍是未知的。一组证据表明，这些化合物 由于G蛋白信号偏向，表现出更好的副作用。然而，最近的工作已经 挑战这一地位的证据表明，这些新的激动剂只是部分激动剂 莫尔。因此，体外研究机制的结果是相互矛盾的，而体内研究是 缺乏。这项建议的目的是研究一系列G蛋白偏向的MOR激动剂在临床前 治疗和副作用的模型，并在实验条件下设计以区分典型和 部分MOR激动剂。在这些条件下，典型的MOR激动剂产生最大幅度的作用， 而部分MOR激动剂产生的作用幅度低于最大值。具体来说，目标1将衡量 新型吗啡受体激动剂与典型吗啡受体激动剂和部分吗啡受体激动剂的镇痛强度比较 在不同程度的热伤害性刺激下进行热板实验。目标2将测量震级 新型MOR激动剂与典型和部分MOR激动剂产生的呼吸抑制的比较 在全身体积描记测试中。目标3将比较最大断点(滥用指标 易感性)由典型的、部分的和新型的MOR激动剂介导的自我给药试验 由累进比率增援计划提供的可操作性挑战水平。根据配置文件 由新的MOR激动剂产生的行为效应，我们将能够确定在体外 是在活体内最接近的概括。最终，我们来自这三个目标的发现将为发展提供信息 阿片类药物治疗具有更有利的安全概况和更广泛的治疗窗口。要完成 这些目标，培训计划在这项建议中描述，并将在杰克逊校区进行 密西西比大学医学中心的。申请者将接受科学培训和 发起人、发起人的合作者、神经科学项目和 健康科学研究生院。