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

摘要 物质使用障碍（SUD）在美国已达到流行病水平[Mack et al 2017]，而且这种情况还在加速 努力寻找有效的药物疗法。所有SUD都与突触多巴胺增加有关， 中脑边缘通路这使得多巴胺转运蛋白（DAT）成为主要的分子靶点，并且是“非典型的”。 DAT抑制剂滥用可能性低，是最有前景的治疗候选药物[Reith et al 2015]。 半边莲碱是一种来自半边莲的复合生物碱，是一种新型非典型DAT抑制剂[Brown et al 2015]， 是SUD药物治疗的领先者。然而，洛宾那林的化学合成是具有挑战性的，因此， 申请人使用专有技术来优化突变体L中的这种前导。红雀属植物细胞[Brown et al 2016年]。这鉴定了两种比山扁豆碱更易溶于水的山扁豆碱N-氧化物， 用不同的方式。像洛宾那林一样，它们是DAT的竞争性抑制剂，但矛盾的是， 与山胡椒碱不同，它们还增加DA摄取能力。这种独特的动作组合非常适合 逆转与SUD相关的突触DA效应，而无内在增强效应或促发 戒断因此，山扁豆碱及其N-氧化物是所有SUD的潜在治疗药物。但在 除了对DAT的活性外，洛宾那林对烟碱受体具有部分激动剂活性[Brown et al 2015]， 这表明在尼古丁和酒精使用障碍中具有特定价值[Rahman et al 2016]。目前， 全球最具破坏性的SUD [Peacock et al，2018]，戒烟也是最有利可图的 SUD治疗市场。支持了山胡椒碱和氮氧化物在这些SUD中的潜在价值 通过简单动物模型中的活性，本IIB期SBIR提案将开始其开发， 治疗学目的是：（1）测试山胡椒碱和N-氧化物的“脱靶”活性，并评估它们的活性。 啮齿类动物单次给药的药代动力学和毒性，（2）在动物模型中更全面地评估它们 （包括尼古丁加酒精自我给药的新大鼠模型），（3）用于增强尼古丁和酒精的剂量的方法， Lobinaline的生物合成及其向N-氧化物的化学转化。商业目标是：（a） 评价这些新的生物合成物作为尼古丁和酒精使用障碍的潜在药物，和（B） 利用这一点将Naprogix生物技术商业化，作为植物先导发现平台。两 在第三阶段，实现这些目标需要与一家大型制药公司或生物技术公司建立伙伴关系。

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.