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.

抽象的物质使用障碍 (SUD) 在美国已达到流行水平 [Mack et al 2017]，而且这一趋势还在加速努力寻找有效的药物疗法。所有 SUD 都与突触多巴胺的增加有关。这使得多巴胺转运蛋白（DAT）成为主要的分子靶标，并且是“非典型的”。 DAT 抑制剂滥用可能性较低，是最有前途的治疗候选药物 [Reith et al 2015]。 Lobinaline 是一种来自半边莲的复杂生物碱，是一种新型非典型 DAT 抑制剂 [Brown et al 2015]，是 SUD 药物治疗的先导药物。然而，lobinaline 的化学合成具有挑战性，因此申请人使用了专有技术来优化突变型 L.cardinalis 植物细胞中的这种先导物质 [Brown 等人 2016]这确定了两种比lobinaline更易溶于水并且还具有调节作用的lobinaline N-氧化物。与洛布那林一样，它们是 DAT 的竞争性抑制剂，但矛盾的是，并且与 lobinaline 不同，它们还可以增加 DA 的吸收能力，这种独特的作用组合非常适合。逆转与 SUD 相关的突触 DA 的影响，无内在强化作用或沉淀因此，洛比那林及其 N-氧化物是所有 SUD 的潜在治疗剂。除了对 DAT 的活性外，lobinaline 对烟碱受体还具有部分激动剂活性 [Brown et al 2015]，这表明对尼古丁和酒精使用障碍具有特定价值 [Rahman et al 2016]。全世界最具破坏性的 SUD [Peacock et al, 2018]，戒烟也是最有利可图的 SUD 治疗市场中的洛布那林和 N-氧化物的潜在价值得到了支持。通过简单动物模型的活动，这一阶段 IIB SBIR 提案将开始其开发治疗的目的是：(1) 测试洛布那林和 N-氧化物的“脱靶”活性，并评估它们的活性。啮齿类动物的单剂量药代动力学和毒性，(2) 在动物模型中更全面地评估它们（包括一种新型的尼古丁加酒精自我给药的大鼠模型），（3）扩大方法洛比那林的生物合成及其化学转化为N-氧化物的商业目标是：(a) 评估这些新型生物合成药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 生物技术作为植物先导化合物发现平台进行商业化。第三阶段的目标将需要与一家大型制药或生物技术公司合作。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Target-directed evolution of novel modulators of the dopamine transporter in Lobelia cardinalis hairy root cultures.

半边莲毛状根培养物中多巴胺转运蛋白新型调节剂的靶向进化。

DOI：
发表时间：
2021-12-10
期刊：
影响因子：
4.1
作者：
Rogers, Dennis T;Pomerleau, Francois;Kelley, Zachary;Brown, Dustin;Lynn, Bert;Gerhardt, Greg A;Littleton, John
通讯作者：
Littleton, John

Microfluidic capillary zone electrophoresis mass spectrometry analysis of alkaloids in Lobelia cardinalis transgenic and mutant plant cell cultures.

半边莲转基因和突变植物细胞培养物中生物碱的微流体毛细管区带电泳质谱分析。