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Novel modulators of the dopamine transporter for alcohol and nicotine use disorders

用于治疗酒精和尼古丁使用障碍的多巴胺转运蛋白的新型调节剂

基本信息

批准号：
10390456
负责人：
Cindy Ann Burklow
金额：
$ 96.64万
依托单位：
NAPROGENIX, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-22 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390456
关键词：
Agonist Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Alkaloids Anabolism Animal Model Animals Biotechnology Bupropion Cell Culture Techniques Cells Chemicals Commercial Sectors Complex Development Directed Molecular Evolution Disclosure Dopamine Dose Drug Addiction Drug Kinetics Epidemic FDA approved Human Intention Lead Libraries Lobelia Methods Modeling Molecular Target Morbidity - disease rate Mutagenesis Nicotine Nicotine Use Disorder Nicotinic Receptors Oxides Parents Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Phase Plants Production Proteins Rattus Recording of previous events Research Rodent Self Administration Small Business Innovation Research Grant Smoking Smoking Cessation Intervention Structure Substance Use Disorder Synapses Technology Technology Transfer Testing Therapeutic Therapeutic Agents Therapeutic Human Experimentation Toxic effect Water Withdrawal Work abuse liability alcohol abuse therapy alcohol use disorder base cathinone chemical synthesis commercialization conditioned place preference cost cytisine dopamine transporter drug discovery effective therapy in vitro testing inhibitor interest invention lead optimization monoamine mouse model mutant nicotine use novel novel therapeutics product development receptor scale up screening smoking cessation social success therapeutic candidate therapeutic target uptake varenicline

项目摘要

Abstract Substance use disorders (SUDs) are at epidemic levels in the US [Mack et al 2017] and this has accelerated efforts to find effective pharmacotherapies. All SUDs are associated with increased synaptic dopamine in the mesolimbic pathway. This makes the dopamine transporter (DAT) a primary molecular target, and “atypical” DAT inhibitors, with low abuse potential, are the most promising therapeutic candidates [Reith et al 2015]. Lobinaline, a complex alkaloid from Lobelia cardinalis, is a novel atypical DAT inhibitor [Brown et al 2015], and is a lead for pharmacotherapy of SUDs. However, chemical synthesis of lobinaline is challenging, so the applicants used a proprietary technology to optimize this lead in mutant L. cardinalis plant cells [Brown et al 2016]. This identified two lobinaline N-oxides that are more water soluble than lobinaline, and also modulate the DAT in a different way. Like lobinaline they are competitive inhibitors of the DAT, but paradoxically, and unlike lobinaline, they also increase DA uptake capacity. This unique combination of actions is ideally suited to reversing effects on synaptic DA associated with SUDs without intrinsic reinforcing effects or precipitating withdrawal. Thus, lobinaline and its N-oxides are potential therapeutic agents for all SUDs. However, in addition to activity on the DAT, lobinaline has partial agonist activity at nicotinic receptors [Brown et al 2015], which suggests specific value in nicotine and alcohol use disorders [Rahman et al 2016]. These are currently the most damaging SUDs worldwide [Peacock et al, 2018], and smoking cessation is also the most profitable market in SUD therapeutics. The potential value of lobinaline and the N-oxides in these SUDs was supported by activity in simple animal models, and this phase IIB SBIR proposal is to begin their development as therapeutics. The aims are; (1) to test lobinaline and the N-oxides for “off-target” activity, and to assess their single dose pharmacokinetics and toxicity in rodents, (2) to evaluate them more fully in animal models (including a novel rat model of nicotine plus alcohol self-administration), (3) to scale-up methods for biosynthesis of lobinaline, and its chemical conversion to the N-oxides. The commercial objectives are: (a) to evaluate these novel biosynthetics as potential medications for nicotine and alcohol use disorders, and (b) to leverage this into the commercialization of Naprogenix biotechnology as a plant lead discovery platform. Both objectives will require partnership with a major pharmaceutical or biotechnology company in phase III.

摘要物质使用障碍(SODS)在美国处于流行水平[Mack等人2017年]，而且这一趋势正在加速努力寻找有效的药物疗法。所有的肥胖症都与突触中增加的多巴胺有关。中脑边缘通路。这使得多巴胺转运体(DAT)成为主要的分子靶标，并且是“非典型的” DAT抑制剂具有较低的滥用潜力，是最有希望的治疗候选药物[Reith等人2015年]。 Lobinaline是一种来自红衣藻的复杂生物碱，是一种新型的非典型DAT抑制剂[Brown等人2015年]，以及是肥皂水药物治疗的先导。然而，化学合成茶碱是具有挑战性的，所以申请者使用了一种专利技术来优化突变的红衣藻植物细胞中的这种领先优势[Brown等人 2016年]。这确定了两个比叶黄碱更易溶于水的叶黄碱N-氧化物，并且也调制了 DAT以一种不同的方式。和洛布林一样，它们也是DAT的竞争性抑制剂，但矛盾的是，与叶黄碱不同的是，它们还增加了DA的摄取能力。这种独特的动作组合非常适合于无固有强化效应或沉淀的SODS对突触DA的逆转作用戒烟。因此，洛布林及其N-氧化物是治疗所有肥皂症的潜在药物。但是，在除DAT上的活性外，洛布林还具有部分尼古丁受体激动剂活性[Brown等人2015年]，这表明了尼古丁和酒精使用障碍的特殊价值[Rahman等人2016年]。这些都是目前全球最具破坏性的肥皂水[孔雀等人，2018]，戒烟也是最有利可图的苏氏疗法的市场。这些肥皂中的茶碱和N-氧化物的潜在价值得到了支持。通过在简单动物模型中的活动，和这个IIB阶段SBIR提案是开始它们的发展作为治疗学。其目的是：(1)测试茶碱和N-氧化物的“脱靶”活性，并评估它们的单次给药在啮齿动物体内的药代动力学和毒性，(2)在动物模型中更全面地评价它们 (包括一种新的尼古丁加酒精自我给药的大鼠模型)，(3)放大方法叶黄碱的生物合成及其化学转化为N-氧化物。商业目标是：(A) 评估这些新的生物合成物作为治疗尼古丁和酒精使用障碍的潜在药物，以及(B) 利用这一点，将Naprogenix生物技术作为植物铅发现平台进行商业化。两者都有目标将需要在第三阶段与一家主要的制药或生物技术公司建立伙伴关系。