Using in-vivo Real-time Biosensor to Evaluate Prodrugs Designed to Prolong Therapeutic Effects for Smoking Cessation.

使用体内实时生物传感器评估旨在延长戒烟治疗效果的前药。

基本信息

批准号：
10546293
负责人：
John Nicholas Betley
金额：
$ 31.86万
依托单位：
SPACERX LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546293
关键词：
Abstinence Address Affect Aftercare Animals Behavior Behavior assessment Behavioral Biological Assay Biological Availability Biological Markers Biosensing Techniques Biosensor Brain Central Nervous System Central Nervous System Agents Circulation Clinical Collaborations Corpus striatum structure Data Development Disease Dopamine Dose Drug Exposure Drug Kinetics Drug Targeting Ensure FDA approved Future Goals Grant Health Intravenous Kinetics Knowledge Laboratories Maximum Tolerated Dose Measurement Measures Methodology Modeling Monitor Mus Neurotransmitters Nicotine Nicotine Dependence Opioid Oral Oral Administration Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Physiological Plasma Positioning Attribute Prodrugs Property Publishing Research Rewards Rodent Seizures Self Administration Signal Transduction Smoking Smoking Cessation Intervention Specificity System Technology Testing Therapeutic Effect Time analog commercial application commercialization compliance behavior craving design drug candidate drug development drug discovery drug efficacy efficacy evaluation experience improved in vivo in vivo monitoring neural next generation nicotine craving nicotine self-administration nicotine use novel novel strategies novel therapeutics pleasure pre-clinical predictive marker premature response screening sensor side effect smoking cessation standard of care varenicline

项目摘要

ABSTRACT Developing drugs that target the central nervous system (CNS) is hampered by an inability to perform direct in vivo preclinical measurements. Here, we propose to identify an optimal smoking cessation drug candidate by monitoring how our newly synthesized prodrugs alter real-time brain dopamine responses to nicotine. Varenicline (CHANTIX®) is the leading FDA-approved oral medication for smoking cessation. However, only 22% of patients maintain abstinence for 52 weeks following varenicline treatment1 and 67% of patients stop treatment prematurely2, suggesting that therapies with better patient compliance are needed. To address this need, we recently developed extended-release prodrugs that are designed to improve the pharmacokinetic properties of varenicline. Varenicline reduces nicotine craving and use by dual action: first providing a transient increase in dopamine levels and subsequently by blocking the dopamine response to nicotine3-5. These changes aim to stabilize dopamine signaling in the brain to achieve two goals: (1) reduce the side effects of transiently dopamine increases and (2) prolong the duration with which the drug reduces the reward value of nicotine. In this Phase I grant, we will use an in vivo dopamine biosensor to evaluate real-time dopamine levels in the striatum (a reward center in the brain) following administration of our novel prodrugs. We will establish an in vivo relationship between brain efficacy (as defined by dopamine release) and drug levels in circulation. These studies will allow us to screen for prodrugs that have optimal efficacy for altering both the level and duration of dopamine response, which we use as a biomarker for predicting efficacy for smoking cessation. The primary hypothesis of this Phase I grant is that a prodrug that stabilizes the initial dopamine release in the striatum while also more efficiently blocking subsequent dopamine responses to nicotine will be more effective than varenicline at decreasing IV self-administration of nicotine. We will test this hypothesis by: 1) establishing pharmacokinetics for each prodrug relative to varenicline; 2) measuring striatal dopamine levels using real-time in vivo biosensors to determine how different exposure curves affect dopamine response; and 3) assessing behavioral changes in response to the prodrugs using a well-established nicotine addiction model. Our initial pilot data demonstrate that, in comparison to varenicline, our prodrugs favorably alter the dopamine release profile in the striatum. Thus, our prodrug approach changes the physiological function of the reward system and may be a better drug for clinical use. Importantly, the core technology used in this grant to develop improved smoking cessation drugs can be utilized more broadly as a general pharmacodynamic assay for CNS drug development. Therefore, this research will provide a platform for drug discovery using in vivo real- time methodologies. SpaceRx has extensive experience making varenicline analogs and prodrugs, and real- time biosensing and measuring neural activity dynamics is a core technology of the Betley laboratory, making our team ideally suited to test our hypothesis to successfully develop novel smoking cessation drugs.

抽象的开发针对中枢神经系统 (CNS) 的药物因无法直接发挥作用而受到阻碍在这里，我们建议通过体内临床前测量来确定最佳的戒烟药物候选者。监测我们新合成的前药如何改变大脑对尼古丁的实时多巴胺反应。 Varenicline (CHANTIX®) 是 FDA 批准的主要戒烟口服药物。 22% 的患者在伐尼克兰治疗后保持禁欲 52 周1，67% 的患者停止戒烟过早治疗2，表明需要患者依从性更好的治疗方法来解决这个问题。根据需要，我们最近开发了缓释前药，旨在改善药代动力学伐尼克兰的特性伐尼克兰通过双重作用减少尼古丁的渴望和使用：首先提供短暂的作用。增加多巴胺水平，随后阻断多巴胺对尼古丁的反应3-5。改变的目的是稳定大脑中的多巴胺信号传导，以实现两个目标：（1）减少副作用短暂的多巴胺增加并且（2）延长药物降低奖励值的持续时间在第一阶段资助中，我们将使用体内多巴胺生物传感器来评估实时多巴胺水平。在给予我们的新型前药后，我们将在纹状体（大脑中的奖励中心）中建立。脑功效（由多巴胺释放定义）与循环中药物水平之间的体内关系。这些研究将使我们能够筛选具有最佳功效的前药，以改变水平和多巴胺反应的持续时间，我们将其用作预测戒烟效果的生物标志物。这一第一阶段资助的主要假设是，有一种前药可以稳定多巴胺的初始释放。纹状体同时也更有效地阻断随后的多巴胺对尼古丁的反应将更有效与伐尼克兰相比，减少静脉注射尼古丁的效果更好。我们将通过以下方式检验这一假设：1) 建立。每种前药相对于伐尼克兰的药代动力学；2) 实时测量纹状体多巴胺水平；体内生物传感器以确定不同的暴露曲线如何影响多巴胺反应；3) 评估；使用我们最初的完善的尼古丁成瘾模型来响应前药的行为变化。试验数据表明，与伐尼克兰相比，我们的前药可以有利地改变多巴胺的释放因此，我们的前药方法改变了奖励系统的生理功能。并且可能是一种更好的临床使用药物，重要的是本次资助所使用的核心技术。改进的戒烟药物可以更广泛地用作一般药效学测定因此，这项研究将为利用体内真实药物发现提供一个平台。 SpaceRx 在制造伐尼克兰类似物和前药以及实时方法方面拥有丰富的经验。时间生物传感和测量神经活动动态是贝特利实验室的核心技术，使得我们的团队非常适合测试我们的假设，以成功开发新型戒烟药物。