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.

抽象的无法直接执行中枢神经系统（CNS）的靶向中枢神经系统（CNS）的药物受到阻碍体内临床前测量。在这里，我们建议通过监视我们新合成的前药如何改变对尼古丁的实时脑多巴胺反应。 Varenicline（Chantix®）是用于戒烟的领先FDA批准的口服药物。但是，只有 22％的患者在Varenicline治疗后52周保持禁欲1和67％的患者停止过早治疗2，表明需要具有更好患者依从性的治疗。解决这个问题需求，我们最近开发了旨在改善药代动力学的扩展释放前药 Varenicline的性质。 Varenicline减少尼古丁的渴望和使用双重动作：首先提供瞬态多巴胺水平的增加，然后通过阻止多巴胺对尼古丁3-5的反应。这些旨在稳定大脑中多巴胺信号的变化以实现两个目标：（1）减少瞬时多巴胺增加，（2）延长药物减少奖励值的持续时间尼古丁。在此阶段I赠款中，我们将使用体内多巴胺生物传感器评估实时多巴胺水平在我们的新型前药执行后，在纹状体（大脑中的奖励中心）中。我们将建立脑效率（由多巴胺释放定义）与循环中的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效率以改变水平和水平和多巴胺反应的持续时间，我们将其用作预测戒烟效率的生物标志物。该阶段I授予的主要假设是，稳定初始多巴胺释放的前药纹状体同时更有效地阻止随后对尼古丁的多巴胺反应更有效降低尼古丁的静脉自我给药时而不是varenicline。我们将通过：1）建立这一假设每种前药相对于Varenicline的药代动力学； 2）使用实时测量纹状体多巴胺水平体内生物传感器确定不同的暴露曲线如何影响多巴胺反应； 3）评估行为变化使用良好的尼古丁成瘾模型对前药的响应发生变化。我们的最初试验数据表明，与Varenicline相比，我们的前药有利地改变了多巴胺的释放纹状体中的轮廓。这，我们的前药方法改变了奖励系统的身体功能并且可能是临床使用的更好的药物。重要的是，该赠款中用于开发的核心技术可以更广泛地将戒烟药物作为一种普通药效测定 CNS药物开发。因此，这项研究将提供一个使用体内实现的药物发现平台时间方法。 SPACERX具有丰富的经验，可以制作Varenicline类似物和前药，并且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，使我们的团队非常适合检验我们的假设，以成功开发新的戒烟药物。